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Methods and compositions for systemically or locally administering a
beneficialagent to a subject are described, and include, for example,
depot gel compositions that can be injected into a desired location and
which can provide controlled release of a beneficial agent over a
prolonged duration of time. The compositions include a biocompatible
polymer, a biocompatible solvent having low water miscibility that forms
a viscous gel with the polymer and limits water uptake by the implant,
and a beneficial agent.

1. An injectable depot composition for sustained delivery of a beneficial
agent to a subject in a controlled manner over a predetermined duration
of time after administration comprising: (a) a viscous gel formulation
comprising: (1) a bioerodible, biocompatible polymer; and (2) a solvent
having a miscibility in water of less than or equal to 7 wt. % at
25.degree. C., in an amount effective to plasticize the polymer and form
a gel therewith; and (b) a beneficial agent dissolved or dispersed in the
gel; wherein said duration of time is from about two weeks to about
twelve months after administration.

2. The composition of claim 1, wherein the polymer is a copolymer of
lactic acid and glycolic acid.

3. The composition of claim 1, wherein the polymer is a polylactide.

4. The composition of claim 1, wherein the polymer is a caprolactone-based
polymer.

5. The composition of claim 1, wherein the polymer is a lactic acid-based
polymer.

6. The composition of claim 2, wherein the polymer has L/G ratio of about
50:50 to about 100:0 and a molecular weight ranging from about 3,000 to
about 120,000.

7. The composition of claim 1 comprising about 5 wt. % to about 90 wt. %
of said biodegradable, biocompatible polymer.

8. The composition of claim 7, comprising about 25 wt. % to about 80 wt. %
of said biodegradable, biocompatible polymer.

9. The composition of claim 7, comprising about 35 wt. % to about 75 wt. %
of said biodegradable, biocompatible polymer.

10. The composition of claim 1, wherein said duration of time is equal to
or greater than three months after administration.

11. The composition of claim 1, wherein said duration of time is from
about 3 months to about 6 months after administration.

12. The composition of claim 1, wherein said duration of time is from
about 3 months to about 9 months after administration.

13. The composition of claim 1, wherein said duration of time is from
about 6 months to about 9 months after administration.

17. The composition of claim 1 wherein the solvent is selected from an
aromatic alcohol, lower alkyl and aralkyl esters of aryl acids; aryl,
aralkyl and lower alkyl ketones; and lower alkyl esters of citric acid.

18. The composition of claim 1 wherein the solvent is benzyl alcohol.

19. The composition of claim 1 wherein the solvent is benzyl benzoate.

20. The composition of claim 1 wherein the solvent is ethyl benzoate.

21. The composition of claim 1, wherein the composition is free of
solvents having a miscibility in water that is greater than 7 wt. % at
25.degree. C.

22. The composition of claim 1, wherein said delivery is a systemic
delivery.

23. The composition of claim 1, wherein said delivery is a local delivery.

24. The composition of claim 1, wherein said delivery is repeated after a
period of time.

25. The composition of claim 1, wherein said delivery is provided at
multiple sites.

26. An injectable depot composition for sustained delivery of a beneficial
agent to a subject in a controlled manner over a predetermined duration
of time after administration comprising: (a) a viscous gel formulation
comprising: (1) a bioerodible, biocompatible polymer; and (2) a solvent
having a miscibility in water of less than or equal to 7 wt. % at
25.degree. C., in an amount effective to plasticize the polymer and form
a gel therewith; and (b) a beneficial agent dissolved or dispersed in the
gel; wherein the beneficial agent is delivered systemically in a
controlled manner over a duration of time is from about two weeks to
about twelve months after administration.

27. The composition of claim 26, wherein the polymer is a copolymer of
lactic acid and glycolic acid.

28. The composition of claim 26, wherein the polymer is a polylactide.

29. The composition of claim 26, wherein the polymer is a
caprolactone-based polymer.

30. The composition of claim 26, wherein the polymer is a lactic
acid-based polymer.

31. The composition of claim 27, wherein the polymer has L/G ratio of
about 50:50 to about 100:0 and a molecular weight ranging from about
3,000to about 120,000.

32. The composition of claim 26, comprising about 5 wt. % to about 90 wt.
% of said biodegradable, biocompatible polymer.

33. The composition of claim 32, comprising about 25 wt. % to about 80 wt.
% of said biodegradable, biocompatible polymer.

34. The composition of claim 32, comprising about 35 wt. % to about 75 wt.
% of said biodegradable, biocompatible polymer.

35. The composition of claim 26, wherein said duration of time is equal to
or greater than three months after administration.

36. The composition of claim 26, wherein said duration of time is from
about 3 months to about 6 months after administration.

37. The composition of claim 26, wherein said duration of time is from
about 3 months to about 9 months after administration.

38. The composition of claim 26, wherein said duration of time is from
about 6 months to about 9 months after administration.

42. The composition of claim 26, wherein the solvent is selected from an
aromatic alcohol, lower alkyl and aralkyl esters of aryl acids; aryl,
aralkyl and lower alkyl ketones; and lower alkyl esters of citric acid.

43. The composition of claim 26, wherein the solvent is benzyl alcohol.

44. The composition of claim 26, wherein the solvent is benzyl benzoate.

45. The composition of claim 26, wherein the solvent is ethyl benzoate.

46. The composition of claim 26, wherein the composition is free of
solvents having a miscibility in water that is greater than 7 wt. % at
25.degree. C.

47. The composition of claim 26, wherein said delivery is repeated after a
period of time.

48. The composition of claim 26, wherein said delivery is provided at
multiple sites.

49. An injectable depot composition for sustained delivery of a beneficial
agent to a subject in a controlled manner over a predetermined duration
of time after administration comprising: (a) a viscous gel formulation
comprising: (1) a bioerodible, biocompatible polymer polymer; and (2) a
solvent having a miscibility in water of less than or equal to 7 wt. % at
25.degree. C., in an amount effective to plasticize the polymer and form
a gel therewith; and (b) a beneficial agent dissolved or dispersed in the
gel; wherein the beneficial agent is delivered locally in a controlled
manner over a duration of time is from about two weeks to about twelve
months after administration.

50. The composition of claim 49, wherein the polymer is a copolymer of
lactic acid and glycolic acid.

51. The composition of claim 49, wherein the polymer is a polylactide.

52. The composition of claim 49, wherein the polymer is a
caprolactone-based polymer.

53. The composition of claim 49, wherein the polymer is a lactic
acid-based polymer.

54. The composition of claim 49, wherein the polymer has L/G ratio of
about 50:50 to about 100:0 and a molecular weight ranging from about
3,000 to about 120,000.

55. The composition of claim 49, comprising about 5 wt. % to about 90 wt.
% of said biodegradable, biocompatible polymer.

56. The composition of claim 55, comprising about 25 wt. % to about 80 wt.
% of said biodegradable, biocompatible polymer.

57. The composition of claim 56, comprising about 35 wt. % to about 75 wt.
% of said biodegradable, biocompatible polymer.

58. The composition of claim 49, wherein said duration of time is equal to
or greater than three months after administration.

59. The composition of claim 49, wherein said duration of time is from
about 3 months to about 6 months after administration.

60. The composition of claim 49, wherein said duration of time is from
about 3 months to about 9 months after administration.

61. The composition of claim 49, wherein said duration of time is from
about 6 months to about 9 months after administration.

65. The composition of claim 49, wherein the solvent is selected from an
aromatic alcohol, lower alkyl and aralkyl esters of aryl acids; aryl,
aralkyl and lower alkyl ketones; and lower alkyl esters of citric acid.

66. The composition of claim 49, wherein the solvent is benzyl alcohol.

67. The composition of claim 49, wherein the solvent is benzyl benzoate.

68. The composition of claim 49, wherein the solvent is ethyl benzoate.

69. The composition of claim 49, wherein the composition is free of
solvents having a miscibility in water that is greater than 7 wt. % at
25.degree. C.

70. The composition of claim 49, wherein said delivery is repeated after a
period of time.

71. The composition of claim 49, wherein said delivery is provided at
multiple sites.

72. A method of administering a beneficial agent to a subject in a
controlled manner over a predetermined duration of time after
administration comprising: (i) administering to a subject: (a) a viscous
gel formulation comprising: (1) a bioerodible, biocompatible polymer
polymer; and (2) a solvent having a miscibility in water of less than or
equal to 7 wt. % at 25.degree. C., in an amount effective to plasticize
the polymer and form a gel therewith; and (b) a beneficial agent
dissolved or dispersed in the gel; and (ii) delivering the beneficial
agent to the subject over a duration of time from about two weeks to
about twelve months after administration.

73. The method of claim 72, further comprising systemically delivering the
beneficial agent to the subject in a controlled manner.

74. The method of claim 72, further comprising repeating the delivering
step (ii) after a period of time.

75. The method of claim 73, further comprising repeating the delivering
step (ii) after a period of time.

76. The method of claim 72, further comprising locally delivering the
beneficial agent to the subject in a controlled manner.

77. The method of claim 76, further comprising repeating the delivery step
(ii) after a period of time.

78. The method of claim 76, further comprising conducting the delivery
step (ii) at multiple sites.

79. A kit for administration of for sustained delivery of a beneficial
agent to a subject in a controlled manner over a predetermined duration
of time after administration comprising: (a) a bioerdible, biocompatible
polymer polymer; (b) a solvent having a miscibility in water of less than
or equal to 7 wt. % at 25.degree. C., in an amount effective to
plasticize the polymer and form a gel therewith; (c) a beneficial agent
dissolved or dispersed in the gel; and optionally, one or more of the
following: (d) an emulsifying agent; (e) a pore former; (f) a solubility
modulator for the beneficial agent, optionally associated with the
beneficial agent; and (g) an osmotic agent; wherein at least the
beneficial agent, optionally associated with the solubility modulator, is
maintained separated from the solvent until the time of administration of
the beneficial agent to a subject.

80. An injectable depot composition for sustained delivery of a beneficial
agent to a subject in a controlled manner over a predetermined duration
of time after administration comprising: (a) a viscous gel formulation
comprising: (1) a bioerodible, biocompatible blend of polymers; and (2) a
solvent having a miscibility in water of less than or equal to 7 wt. % at
25.degree. C., in an amount effective to plasticize the polymers and form
a gel therewith; and (b) a beneficial agent dissolved or dispersed in the
gel; wherein said duration of time is from about two weeks to about
twelve months after administration.

81. The composition of claim 80, wherein the blend of polymers include a
copolymer of lactic acid and glycolic acid.

82. The composition of claim 80, wherein the blend of polymers include a
polylactide.

83. The composition of claim 80, wherein the blend of polymers include a
caprolactone-based polymer.

84. The composition of claim 80, wherein the blend of polymers include a
polymer having an L/G ratio of about 50:50 to about 100:0 and a molecular
weight ranging from about 3,000to about 120,000.

85. The composition of claim 80, comprising about 5 wt. % to about 90 wt.
% of said biodegradable, biocompatible polymer.

86. The composition of claim 85, comprising about 25 wt. % to about 80 wt.
% of said biodegradable, biocompatible polymer.

87. The composition of claim 85, comprising about 35 wt. % to about 75 wt.
% of said biodegradable, biocompatible polymer.

88. The composition of claim 80, wherein said duration of time is equal to
or greater than three months after administration.

89. The composition of claim 80, wherein said duration of time is from
about 3 months to about 6 months after administration.

90. The composition of claim 80, wherein said duration of time is from
about 3 months to about 9 months after administration.

91. The composition of claim 80, wherein said duration of time is from
about 6 months to about 9 months after administration.

95. The composition of claim 80, wherein the solvent is selected from an
aromatic alcohol, lower alkyl and aralkyl esters of aryl acids; aryl,
aralkyl and lower alkyl ketones; and lower alkyl esters of citric acid.

96. The composition of claim 80, wherein the solvent is benzyl alcohol.

97. The composition of claim 80, wherein the solvent is benzyl benzoate.

98. The composition of claim 80, wherein the solvent is ethyl benzoate.

99. The composition of claim 80, wherein the composition is free of
solvents having a miscibility in water that is greater than 7 wt. % at
25.degree. C.

100. The composition of claim 80, wherein said delivery is a systemic
delivery.

101. The composition of claim 80, wherein said delivery is a local
delivery.

102. The composition of claim 80, wherein said delivery is repeated after
a period of time.

103. The composition of claim 80, wherein said delivery is provided at
multiple sites.

104. An injectable depot composition for sustained delivery of a
beneficial agent to a subject in a controlled manner over a predetermined
duration of time after administration comprising: (a) a viscous gel
formulation comprising: (1) a bioerodible, biocompatible blend of
polymers; and (2) a solvent having a miscibility in water of less than or
equal to 7 wt. % at 25.degree. C., in an amount effective to plasticize
the polymers and form a gel therewith; and (b) a beneficial agent
dissolved or dispersed in the gel; wherein the beneficial agent is
delivered systemically in a controlled manner over a duration of time is
from about two weeks to about twelve months after administration.

105. An injectable depot composition for sustained delivery of a
beneficial agent to a subject in a controlled manner over a predetermined
duration of time after administration comprising: (a) a viscous gel
formulation comprising: (1) a bioerodible, biocompatible blend of
polymers; and (2) a solvent having a miscibility in water of less than or
equal to 7 wt. % at 25.degree. C., in an amount effective to plasticize
the polymers and form a gel therewith; and (b) a beneficial agent
dissolved or dispersed in the gel; wherein the beneficial agent is
delivered locally in a controlled manner over a duration of time is from
about two weeks to about twelve months after administration.

106. A method of administering a beneficial agent to a subject in a
controlled manner over a predetermined duration of time after
administration comprising: (ii) administering to a subject: (a) a viscous
gel formulation comprising: (1) a bioerodible, biocompatible blend of
polymers; and (2) a solvent having a miscibility in water of less than or
equal to 7 wt. % at 25.degree. C., in an amount effective to plasticize
the polymers and form a gel therewith; and (b) a beneficial agent
dissolved or dispersed in the gel; and (ii) delivering the beneficial
agent to the subject over a duration of time from about two weeks to
about twelve months after administration.

107. The method of claim 106, further comprising systemically delivering
the beneficial agent to the subject in a controlled manner.

108. The method of claim 106, further comprising repeating the delivering
step (ii) after a period of time.

109. The method of claim 107, further comprising repeating the delivering
step (ii) after a period of time.

110. The method of claim 106, further comprising locally delivering the
beneficial agent to the subject in a controlled manner.

111. The method of claim 110, further comprising repeating the delivery
step (ii) after a period of time.

112. The method of claim 110, further comprising conducting the delivery
step (ii) at multiple sites.

113. A kit for administration of for sustained delivery of a beneficial
agent to a subject in a controlled manner over a predetermined duration
of time after administration comprising: (a) a bioerodible, biocompatible
blend of polymers; (b) a solvent having a miscibility in water of less
than or equal to 7 wt. % at 25.degree. C., in an amount effective to
plasticize the polymers and form a gel therewith; (c) a beneficial agent
dissolved or dispersed in the gel; and optionally, one or more of the
following: (d) an emulsifying agent; (e) a pore former; (f) a solubility
modulator for the beneficial agent, optionally associated with the
beneficial agent; and (g) an osmotic agent; wherein at least the
beneficial agent, optionally associated with the solubility modulator, is
maintained separated from the solvent until the time of administration of
the beneficial agent to a subject.

Description

[0001] This application claims the benefit of U.S. Provisional Application
No. 60/424,428 filed Nov. 6, 2002; which is incorporated herein by
reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a depot gel composition that can
be injected into a desired location and which can provide controlled
release of a beneficial agent over a specified/desired duration of time.
The present invention also relates to a method of preparing and
administering the composition.

[0004] 2. Description of the Related Art

[0005] Biodegradable polymers have been used for many years in medical
applications. Illustrative devices composed of the biodegradable polymers
include sutures, surgical clips, staples, implants, and drug delivery
systems. The majority of these biodegradable polymers have been based
upon glycolide, lactide, caprolactone, and copolymers thereof.

[0006] The biodegradable polymers can be thermoplastic materials, meaning
that they can be heated and formed into various shapes such as fibers,
clips, staples, pins, films, etc. Alternatively, they can be
thermosetting materials formed by crosslinking reactions, which lead to
high molecular weight materials that do not melt or form flowable liquids
at high temperatures. Although thermoplastic and thermosetting
biodegradable polymers have many useful biomedical applications, there
are several important limitations to their use in the bodies of various
animals including humans, animals, birds, fish, and reptiles.

[0007] Solid implant drug delivery systems containing a drug incorporated
in thermoplastic or thermosetting biodegradable polymers have been widely
used successfully. Such implants have to be inserted into the body
through an incision which is sometimes larger than desired by the medical
profession and occasionally lead to a reluctance of the patients to
accept such an implant or drug delivery system. The following patents
U.S. Pat. Nos. 5,456,679; 5,336,057; 5,308,348; 5,279,608; 5,234,693;
5,234,692; 5,209,746; 5,151,093; 5,137,727; 5,112,614; 5,085,866;
5,059,423; 5,057,318; 4,865,845; 4,008,719; 3,987,790 and 3,797,492 are
believed to be representative of such drug delivery systems and are
incorporated herein by reference. These patents disclose reservoir
devices, osmotic delivery devices and pulsatile delivery devices for
delivering beneficial agents.

[0008] Injecting drug delivery systems as small particles, microspheres,
or microcapsules avoids the incision needed to implant drug delivery
systems. However, these materials do not always satisfy the demand for a
biodegradable implant. These materials are particulate in nature, do not
form a continuous film or solid implant with the structural integrity
needed for certain prostheses, the particles tend to aggregate and thus
their behavior is hard to predict. When inserted into certain body
cavities such as a mouth, a periodontal pocket, the eye, or the vagina
where there is considerable fluid flow, these small particles,
microspheres, or microcapsules are poorly retained because of their small
size and discontinuous nature. Further, if there are complications,
removal of microcapsule or small-particle systems from the body without
extensive surgical intervention is considerably more difficult than with
solid implants. Additionally, manufacture, storage and injectability of
microspheres or microcapsules prepared from these polymers and containing
drugs for release into the body present problems.

[0010] Previously described polymer compositions for injectable implants
have used solvent/plasticizers that are very or relatively soluble in
aqueous body fluids to promote rapid solidification of the polymer at the
implant site and promote diffusion of drug from the implant. Rapid
migration of water into such polymeric implants utilizing water soluble
polymer solvents when the implants are placed in the body and exposed to
aqueous body fluids presents a serious problem. The rapid water uptake
often results in implants having pore structures that are non-homogeneous
in size and shape. Typically, the surface pores take on a finger-like
pore structure extending for as much as one-third of a millimeter or more
from the implant surface into the implant, and such finger-like pores are
open at the surface of the implant to the environment of use. The
internal pores tend to be smaller and less accessible to the fluids
present in the environment of use. The rapid water uptake characteristic
often results in uncontrolled release of beneficial agent that is
manifested by an initial, rapid release of beneficial agent from the
polymer composition, corresponding to a "burst" of beneficial agent being
released from the implant. The burst often results in a substantial
portion of the beneficial agent, if not all, being released in a very
short time, e.g., hours or 1-2 days. Such an effect can be unacceptable,
particularly in those circumstances where a controlled delivery is
desired, i.e., delivery of beneficial agent in a controlled manner over a
period of greater than or equal to a month or up to one year, or where
there is a narrow therapeutic window and release of excess beneficial
agent can result in adverse consequences to the subject being treated, or
where it is necessary to mimic the naturally-occurring daily profile of
beneficial agents, such as hormones and the like, in the body of the
subject being treated.

[0011] Accordingly, when such devices are implanted, the finger-like pores
allow very rapid uptake of aqueous body fluids into the interior of the
implant with consequent immediate and rapid dissolution of significant
quantities of beneficial agent and unimpeded diffusion of beneficial
agent into the environment of use, producing the burst effect discussed
above.

[0012] Furthermore, rapid water uptake can result in premature polymer
precipitation such that a hardened implant or one with a hardened skin is
produced. The inner pores and much of the interior of the polymer
containing beneficial agent are shut off from contact with the body
fluids and a significant reduction in the release of beneficial agent can
result over a not insignificant period of time ("lag time"). That lag
time is undesirable from the standpoint of presenting a controlled,
sustained release of beneficial agent to the subject being treated. What
one observes, then, is a burst of beneficial agent being released in a
short time period immediately after implantation, a lag time in which no
or very little beneficial agent is being released, and subsequently
continued delivery of beneficial agent (assuming beneficial agent remains
after the burst) until the supply of beneficial agent is exhausted.

[0013] Various approaches to control burst and modulate and stabilize the
delivery of the beneficial agent have been described. The following
patents U.S. Pat. Nos. 6,130,200; 5,990,194; 5,780,044; 5,733,950;
5,656,297; 5,654,010; 4,985,404 and 4,853,218 and PCT publication WO
98/27962 are believed to be representative and are incorporated herein by
reference. Notwithstanding some success, those methods have not been
entirely satisfactory for the large number of beneficial agents that
would be effectively delivered by implant.

SUMMARY OF THE INVENTION

[0014] The present invention provides a method and an injectable depot gel
composition for systemic and local delivery of a beneficial agent to a
subject over a prolonged duration of time. In particular, the invention
provides controlled release of the beneficial agent to the subject being
treated, the release being controlled over a period from about, equal to
or greater than two weeks or up to one year after administration, i.e.
from about two weeks to about twelve months after administration,
preferably over a period equal to or greater than one month after
administration or preferably over a period from about one month to about
twelve months after administration; preferably over a period equal to or
greater than 2 months after administration, preferably over a period
equal to or greater than 3 months after administration, preferably over a
period of about 3 months to about 9 months after administration,
preferably over a period of about 3 months to about 6 months after
administration, preferably over a period of up to about 3 months, up to
about 4 months, up to about 5 months; and up to about 6 months after
administration. A single administration of the injectable depot gel
composition provides longer sustained release of active agents over a
prolonged duration of time, thus reducing the frequency of administration
and improving patient compliance. Additionally, the invention provides a
method of preparing the injectable depot gel composition.

[0015] In one aspect, the invention pertains to an injectable depot
composition for sustained delivery of a beneficial agent to a subject in
a controlled manner over a predetermined duration of time after
administration comprising

[0016] (a) a viscous gel formulation comprising:

[0017] (1) a bioerodible, biocompatible polymer, wherein the polymer is a
lactic acid-based polymer; and

[0018] (2) a solvent having a miscibility in water of less than or equal
to 7 wt. % at 25.degree. C., in an amount effective to plasticize the
polymer and form a gel therewith; and

[0019] (b) a beneficial agent dissolved or dispersed in the gel;

[0020] wherein said beneficial agent is delivered over a duration equal to
or greater than one month. Preferably, the polymer is a copolymer of
lactic acid and glycolic acid, having a comonomer ratio (an L/G ratio) of
about 50:50 to about 100:0; and a molecular weight ranging from about
3,000 to about 120,000.

[0021] In another aspect, the invention pertains to an injectable depot
composition for sustained delivery of a beneficial agent to a subject in
a controlled manner over a predetermined duration of time after
administration comprising

[0022] (a) a viscous gel formulation comprising:

[0023] (1) a bioerodible, biocompatible polymer, wherein the polymer is a
lactic acid-based polymer; and

[0024] (2) a solvent having a miscibility in water of less than or equal
to 7 wt. % at 25.degree. C., in an amount effective to plasticize the
polymer and form a gel therewith; and

[0025] (b) a beneficial agent dissolved or dispersed in the gel;

[0026] wherein said beneficial agent is delivered over a duration equal to
or greater than one month. Preferably, the polymer is a copolymer of
lactic acid and a caprolactone-based polymer including caprolactone (CL),
having a comonomer ratio (an L/CL ratio) of about 25:75 to about 75:25;
and a molecular weight ranging from about 3,000 to about 120,000.

[0027] In another aspect, the invention pertains to an injectable depot
composition sustained systemic delivery of a beneficial agent to a
subject in a controlled manner over a duration equal to or greater than
one month after administration comprising (a) a viscous gel formulation
comprising: (1) a bioerodible, biocompatible polymer, wherein the polymer
is a lactic acid-based polymer; and (2) a solvent having a miscibility in
water of less than or equal to 7 wt. % at 25.degree. C., in an amount
effective to plasticize the polymer and form a gel therewith; and (b) a
beneficial agent dissolved or dispersed in the gel.

[0028] In an additional aspect, the invention pertains to an injectable
depot composition for sustained delivery of a beneficial agent to a
subject in a controlled manner over a predetermined duration of time
after administration comprising (a) a viscous gel formulation comprising:
(1) a bioerodible, biocompatible polymer, wherein the polymer is a lactic
acid-based polymer; and (2) a solvent having a miscibility in water of
less than or equal to 7 wt. % at 25.degree. C., in an amount effective to
plasticize the polymer and form a gel therewith; and (b) a beneficial
agent dissolved or dispersed in the gel; wherein the beneficial agent is
delivered systemically in a controlled manner over a duration equal to or
greater than one month after administration.

[0029] In another aspect, the invention pertains to an injectable depot
composition sustained local delivery of a beneficial agent to a subject
in a controlled manner over a duration equal to or greater than one month
after administration comprising (a) a viscous gel formulation comprising:
(1) a bioerodible, biocompatible polymer, wherein the polymer is a lactic
acid-based polymer; and (2) a solvent having a miscibility in water of
less than or equal to 7 wt. % at 25.degree. C., in an amount effective to
plasticize the polymer and form a gel therewith; and (b) a beneficial
agent dissolved or dispersed in the gel.

[0030] In an additional aspect, the invention pertains to an injectable
depot composition for sustained delivery of a beneficial agent to a
subject in a controlled manner over a predetermined duration of time
after administration comprising (a) a viscous gel formulation comprising:
(1) a bioerodible, biocompatible polymer, wherein the polymer is a lactic
acid-based polymer; and (2) a solvent having a miscibility in water of
less than or equal to 7 wt. % at 25.degree. C., in an amount effective to
plasticize the polymer and form a gel therewith; and (b) a beneficial
agent dissolved or dispersed in the gel; wherein the beneficial agent is
delivered locally in a controlled manner over a duration equal to or
greater than one month after administration.

[0031] In another aspect, the invention pertains to an injectable depot
composition as described above, further including at least one of the
following: a pore former; a solubility modulator for the beneficial
agent; and an osmotic agent.

[0033] In another aspect, the invention pertains to an injectable depot
composition as described above, wherein the solvent is selected from an
aromatic alcohol having the structural formula (I)

Ar-(L)n-OH (I)

[0034] in which Ar is a substituted or unsubstituted aryl or heteroaryl
group, n is zero or 1, and L is a linking moiety; and a solvent selected
from the group consisting of esters of aromatic acids, aromatic ketones,
and mixtures thereof.

[0035] In preferred embodiments, the solvent is selected from the aromatic
alcohol, lower alkyl and aralkyl esters of aryl acids; aryl, aralkyl and
lower alkyl ketones; and lower alkyl esters of citric acid. Preferably,
the solvent is selected from benzyl alcohol, benzyl benzoate and ethyl
benzoate. In preferred embodiments, the composition is free of solvents
having a miscibility in water that is greater than 7 wt. % at 25.degree.
C. Preferably the solvent has a miscibility in water of less than 7 wt.
%, more preferably less than 5 wt %, and more preferably less than 3 wt
%.

[0036] In additional aspects, the invention pertains to methods of
administering a beneficial agent to a subject in a controlled manner over
a duration equal to or greater than one month after administration,
comprising administering an injectable depot composition as described
above. In certain embodiments, the beneficial agent is delivered
systemically in a controlled manner over a duration equal to or greater
than one month after administration. In additional embodiments, the
beneficial agent is delivered locally in a controlled manner over a
duration equal to or greater than one month after administration.

[0037] In additional aspects, the invention pertains to a kit for
administration of for sustained delivery of a beneficial agent to a
subject in a controlled manner over a predetermined duration of time
after administration comprising:

[0039] (b) a solvent having a miscibility in water of less than or equal
to 7 wt. % at 25.degree. C., in an amount effective to plasticize the
polymer and form a gel therewith;

[0040] (c) a beneficial agent dissolved or dispersed in the gel; and
optionally, one or more of the following:

[0041] (d) an emulsifying agent;

[0042] (e) a pore former;

[0043] (f) a solubility modulator for the beneficial agent, optionally
associated with the beneficial agent; and

[0044] (g) an osmotic agent;

[0045] wherein at least the beneficial agent, optionally associated with
the solubility modulator, is maintained separated from the solvent until
the time of administration of the beneficial agent to a subject. In
additional embodiments, the kit comprises a metering device, such as
syringe, catheter, pump, syringe pump, autoinjector and the like.

[0046] These and other embodiments of the present invention will readily
occur to those of ordinary skill in the art in view of the disclosure
herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The foregoing and other objects, features and advantages of the
present invention will be more readily understood upon reading the
following detailed description in conjunction with the drawings as
described hereinafter.

[0048] FIG. 1 is a graph illustrating the rheological properties of the
depot formulations of the present invention (formulations 42-45).

[0049] FIG. 2 is a graph illustrating the rheological properties of the
depot formulation of the present invention (formulations 46-48).

[0050] FIG. 3 is a graph illustrating the rheological properties of the
depot formulation of the present invention (formulations 51 and 52).

[0051] FIG. 4 is a graph illustrating the injection forces of the depot
formulations of the present invention (formulations 42-45).

[0052] FIG. 5 is a graph illustrating the injection forces of the depot
formulations of the present invention (formulations 48-50).

[0053] FIG. 6A is a graph illustrating the in vivo release profile of
human growth hormone (hGH) obtained from depot formulations of the
present invention (formulations 21 and 22).

[0054] FIG. 6B is a graph illustrating the in vivo release profile of
human growth hormone obtained from various depot formulations, including
those of the present invention (formulations 29-31).

[0055] FIG. 6C is a graph illustrating the in vivo release profile of
human growth hormone obtained from various depot formulations, including
those of the present invention (formulations 33, 35, 36, 39 and 40).

[0056] FIG. 6D are graphs illustrating the in vivo release profile of
human growth hormone obtained from various depot formulations, including
those of the present invention (formulations 34, 35, 37, 38 and 40).

[0057] FIG. 7 is a graph illustrating the in vivo release profile of
bupivacaine hydrochloride obtained from depot formulations of the present
invention (formulations 17-18).

[0058] FIG. 8 is a graph illustrating the in vivo release profile of
bupivacaine base obtained from depot formulations of the present
invention (formulations 19-20).

[0059] FIG. 9 is a graph illustrating the in vivo release profile of
bupivacaine base obtained from a depot formulation of the present
invention (formulation 20).

[0060] FIG. 10 is a graph illustrating the in vivo release profile of
bupivacaine hydrochloride obtained from depot compositions of the present
invention (formulations 62 and 63).

[0061] FIG. 11 is a graph illustrating the in vivo release profile of
bupivacaine hydrochloride obtained from depot compositions of the present
invention (formulations 64 and 65).

[0062] FIG. 12 is a graph illustrating the in vivo release profile of
bupivacaine hydrochloride obtained from depot compositions of the present
invention (formulations 11 and 12).

[0063] FIG. 13 is a graph illustrating the in vivo release profile of
leuprolide acetate obtained from the depot formulations of the present
invention (formulations 42 and 47) as compared with 3-month Lupron
depots.RTM. (formulation 53).

[0064] FIG. 14 is a graph illustrating the in vivo release profile of
leuprolide acetate obtained from the depot formulations of the present
invention (formulations 42, 43 and 45).

[0065] FIG. 15 is a graph illustrating the in vivo release profile of
leuprolide acetate obtained from the depot formulations of the present
invention (formulations 42 and 49).

[0066] FIG. 16 is a graph illustrating the in vivo release profile of
leuprolide acetate obtained from the depot formulation of the present
invention (formulation 46) as compared with 3-month Lupron depot.RTM.
(formulation 53).

[0067] FIG. 17 is a graph illustrating the in vivo release profile of
leuprolide acetate obtained from the depot formulation of the present
invention (formulations 42, 51 and 52) as compared with 3-month Lupron
depot.RTM. (formulation 53).

[0068] FIG. 18 is a graph illustrating the in vivo release profile of
leuprolide acetate obtained from the 3-month depot formulation of the
present invention (formulations 54 and 55).

[0069] FIG. 19 is a graph illustrating the in vivo suppression of rat
testosterone by the -3 month leuprolide acetate depot formulations of the
present invention (formulations 54 and 55) as compared with the placebo
formulations without leuprolide acetate (formulations 56 and 56).

[0070] FIG. 20 is a graph illustrating the in vivo release profile of
leuprolide acetate obtained from the 6-month depot formulation of the
present invention (formulations 58 and 59).

[0071] FIG. 21 is a graph illustrating the in vivo suppression of rat
testosterone by the 6-month leuprolide acetate depot formulations of the
present invention (formulations 58 and 59) as compared with the placebo
formulations without leuprolide acetate (formulations 60 and 61).

DETAILED DESCRIPTION OF THE INVENTION

[0072] Overview and Definitions:

[0073] The present invention is directed to an injectable depot
composition for delivery of a beneficial agent to a subject over a
prolonged duration of time, at multiple sites if required, and for
multiple or repeated injections, i.e. for instances where the therapeutic
effect of the beneficial agent has subsided or period of time for the
beneficial agent to have a therapeutic effect has lapsed or for instances
where the subject requires further administration of the beneficial agent
for any reason, wherein the injectable depot composition serves as an
implanted sustained release beneficial agent delivery system after
injection into a patient's body. In particular, the invention provides
controlled release of the beneficial agent to the subject being treated,
the release being controlled over a period about, equal to or greater
than two weeks and up to one year after administration, i.e. period of
about two weeks to about twelve months after administration, preferably
over a period equal to or greater than one month after administration;
preferably over a period equal to or greater than 2 months after
administration, preferably over a period equal to or greater than 3
months after administration, preferably over a period of about 3 months
to about 9 months after administration, preferably over a period of about
3 months to about 6 months after administration, preferably over a period
of up to about 3 months, up to about 4 months, up to about 5 months; and
up to about 6 months after administration. The present invention also
relates to a method of using the injectable depot composition to
administer a beneficial agent to a patient.

[0074] The injectable depot composition is a gel formed from a polymer
matrix comprising a bioerodible, biocompatible polymer; a solvent having
a miscibility in water of less than or equal to 7 wt. % at 25.degree. C.,
in an amount effective to plasticize the polymer and form a gel
therewith; and a beneficial agent dissolved or dispersed in the gel. The
present invention is also directed to a method of systemically or locally
administering and delivering a beneficial agent to a subject to include
by implanting in the subject an injectable depot composition as described
above. The method of systemic or local delivery of the present invention
is at multiple sites, if required, and is also directed toward multiple
or repeated injections, i.e. for instances where the therapeutic effect
of the beneficial agent has subsided or period of time for the beneficial
agent to have a therapeutic effect has lapsed or for instances where the
subject requires further administration of the beneficial agent for any
reason,

[0075] By appropriate choice of solvent, water migration from the aqueous
environment surrounding the implant system is restricted, and beneficial
agent is released to the subject over a period of time, thus providing
for delivery of the beneficial agent with a controlled burst of
beneficial agent and sustained release thereafter.

[0076] It has been surprisingly found that the release rate of the
beneficial agent from the injectable depot gel formulations of the
invention can be varied by varying the polymer properties, such as the
type of polymer, the molecular weight of the polymer (including the modal
distribution of the polymer), and the comonomer ratio of the monomers
forming the polymer, the end group of the polymers; the type of solvent;
and by varying the polymer/solvent ratios to provide a controlled,
sustained release of a beneficial agent over a prolonged duration of time
equal to or greater than two weeks and up to one year after
administration, i.e. from about two weeks to about twelve months after
administration, or preferably over a period from about one month to about
twelve months after administration, preferably over a period equal to or
greater than one month after administration; preferably over a period
equal to or greater than 2 months after administration, preferably over a
period equal to or greater than 3 months after administration, preferably
over a period of about 3 months to about 9 months after administration,
preferably over a period of about 3 months to about 6 months after
administration, preferably over a period of up to about 3 months, up to
about 4 months, up to about 5 months; and up to about 6 months after
administration. The release rate profile and duration can be controlled
by the appropriate choice of a polymer (including the ratio of the
monomers, e.g. L/G, CL/L ratios), the molecular weight of the polymer
(LMW, MMW, HMW), the end group of the polymer (acid, ester); a water
immiscible solvent, the polymer/solvent ratio, emulsifying agent, pore
former, solubility modifier for the beneficial agent, an osmotic agent,
and the like.

[0077] Additionally, the present invention provides a method of regulating
the release of a beneficial agent from an injectable depot composition.
The duration and the rate of release of the beneficial agent are
controlled by the appropriate choice of the biodegradable polymer, the
molecular weight of the polymer, the comonomer ratio of the various
monomers forming the polymer (e.g., the L/G or CL/L ratio for a given
polymer), the polymer/solvent ratios, and combinations of these factors,
as described in greater detail below (see also Tables A, B, C and D
below).

[0078] In some embodiments, pore formers and solubility modulators of the
beneficial agent may be added to the implant systems to provide desired
release profiles from the implant systems, along with typical
pharmaceutical excipients and other additives that do not change the
beneficial aspects of the present invention.

[0079] The composition provides controlled sustained release of the
beneficial agent by restricting water migration from the aqueous
environment surrounding the implant system, thus delivering the
beneficial agent over a prolonged duration as described earlier. A single
administration of the injectable depot gel composition provides longer
sustained release of active agents over a prolonged duration of time,
thus reducing the frequency of administration and improving patient
compliance. Because the polymer of the composition is bioerodible, the
implant system does not have to be surgically removed after beneficial
agent is depleted from the implant. Moreover, the polymer of the
composition in accordance with the present invention is bioerodible, it
can be administered both systemically or locally, to include delivery at
multiple sites, if required, and is also usable for multiple or repeated
administrations, such as repeated injections, particularly for instances
where the therapeutic effect of the beneficial agent has subsided or the
period of time for the beneficial agent to have a therapeutic effect has
lapsed or for instances where the subject requires further administration
of the beneficial agent for any reason.

[0080] Generally, the compositions of the invention are gel-like and form
with a substantially homogeneous non-porous structure throughout the
implant upon implantation and during drug delivery, even as it hardens.
Furthermore, while the polymer gel implant will slowly harden when
subjected to an aqueous environment, the hardened implant may maintain a
rubbery (non-rigid) composition with the glass transition temperature Tg
being below 37.degree. C.

[0081] The preferred compositions herein allow beneficial agent to be
loaded into the interior of the polymer at levels that are above that
required to saturate the beneficial agent in water, thereby facilitating
zero order release of beneficial agent. Additionally, the preferred
compositions may provide viscous gels that have a glass transition
temperature that is less than 37.degree. C., such that the gel remains
non-rigid for a period of time after implantation of 24 hours or more.

[0082] It has been discovered that when a solvent having a solubility in
water of less than 7% by weight in water is present in the system,
suitable burst control and sustained delivery of beneficial agent is
achieved, whether or not a solubility modulator of the beneficial agent
is present in the system. Typically, the implant systems useful in this
invention will release, in the first 2 days after implantation, 60% or
less of the total amount of beneficial agent to be delivered to the
subject from the implant system, preferably 50% or less, more preferably
40% or less and even more preferably 30% or less.

[0083] When the composition is intended for implantation by injection, the
viscosity optionally may be modified by addition of emulsifiers or
thixotropic agents to obtain a gel composition having a viscosity low
enough to permit passage of the gel composition through a needle. Also,
pore formers and solubility modulators of the beneficial agent may be
added to the implant systems to provide desired release profiles from the
implant systems, along with typical pharmaceutical excipients and other
additives that do not change the beneficial aspects of the present
invention. The addition of a solubility modulator to the implant system
may enable the use of a solvent having a solubility of 7% or greater in
the implant system with minimal burst and sustained delivery under
particular circumstances. However, it is presently preferred that the
implant system utilize at least one solvent having a solubility in water
of less than 7% by weight, whether the solvent is present alone or as
part of a solvent mixture. It has also been discovered that when mixtures
of solvents which include a solvent having 7% or less by weight
solubility in water and one or more miscible solvents, optionally having
greater solubility, are used, implant systems exhibiting limited water
uptake and minimal burst and sustained delivery characteristics are
obtained.

[0084] Definitions

[0085] In describing and claiming the present invention, the following
terminology will be used in accordance with the definitions set out
below:

[0086] The singular forms "a," "an" and "the" include plural referents
unless the context clearly dictates otherwise. Thus, for example,
reference to "a solvent" includes a single solvent as well as a mixture
of two or more different solvents, reference to "a beneficial agent"
includes a single beneficial agent as well as two or more different
beneficial agents in combination, and the like.

[0087] The term "beneficial agent" means an agent that affects a desired
beneficial, often pharmacological, effect upon-administration to a human
or an animal, whether alone or in combination with other pharmaceutical
excipients or inert ingredients.

[0088] The term "AUC" means the area under the curve obtained from an in
vivo assay in a subject by plotting blood plasma concentration of the
beneficial agent in the subject against time, as measured from the time
of implantation of the composition, to a time "t" after implantation. The
time t will correspond to the delivery period of beneficial agent to a
subject.

[0089] The term "burst index" means, with respect to a particular
composition intended for systemic delivery of a beneficial agent, the
quotient formed by dividing (i) the AUC calculated for the first time
period after implantation of the composition into a subject divided by
the number of hours in the first time period (t1), by (ii) the AUC
calculated for the time period of delivery of beneficial agent, divided
by the number of hours in the total duration of the delivery period (t2).
For example the burst index at 24 hours is the quotient formed by
dividing (i) the AUC calculated for the first twenty-four hours after
implantation of the composition into a subject divided by the number 24,
by (ii) the AUC calculated for the time period of delivery of beneficial
agent, divided by the number of hours in the total duration of the
delivery period.

[0090] The phrase "dissolved or dispersed" is intended to encompass all
means of establishing a presence of beneficial agent in the gel
composition and includes dissolution, dispersion, suspension and the
like.

[0091] The term "systemic" means, with respect to delivery or
administration of a beneficial agent to a subject, that the beneficial
agent is detectable at a biologically-significant level in the blood
plasma of the subject.

[0092] The term "local" means, with respect to delivery or administration
of a beneficial agent to a subject, that the beneficial agent is
delivered to a localized site in the subject but is not detectable at a
biologically significant level in the blood plasma of the subject.

[0093] The terms "prolonged period" or "prolonged duration" are used
interchangeably and refer to a period of time over which release of a
beneficial agent from the depot gel composition of the invention occurs,
which will generally be over a period equal to or greater than two weeks
or up to one year after administration, preferably over a period equal to
or greater than one month after administration; preferably over a period
equal to or greater than 2 months after administration, preferably over a
period equal to or greater than 3 months after administration, preferably
over a period of up to about 3 months to about 9 months after
administration, preferably over a period of up to about 3 months to about
6 months after administration, preferably over a period of up to about 3
months, up to about 4 months, up to about 5 months; and up to about 6
months after administration

[0094] The term "gel vehicle" means the composition formed by mixture of
the polymer and solvent in the absence of the beneficial agent.

[0095] The term "initial burst" means, with respect to a particular
composition of this invention, the quotient obtained by dividing (i) the
amount by weight of beneficial agent released from the composition in a
predetermined initial period of time after implantation, by (ii) the
total amount of beneficial agent that is to be delivered from an
implanted composition. It is understood that the initial burst may vary
depending on the shape and surface area of the implant. Accordingly, the
percentages and burst indices associated with initial burst described
herein are intended to apply to compositions tested in a form resulting
from dispensing of the composition from a standard syringe.

[0096] The term "solubility modulator" means, with respect to the
beneficial agent, an agent that will alter the solubility of the
beneficial agent, with reference to polymer solvent or water, from the
solubility of beneficial agent in the absence of the modulator. The
modulator may enhance or retard the solubility of the beneficial agent in
the solvent or water. However, in the case of beneficial agents that are
highly water soluble, the solubility modulator will generally be an agent
that will retard the solubility of the beneficial agent in water. The
effects of solubility modulators of the beneficial agent may result from
interaction of the solubility modulator with the solvent, or with the
beneficial agent itself, such as by the formation of complexes, or with
both. For the purposes hereof, when the solubility modulator is
"associated" with the beneficial agent, all such interactions or
formations as may occur are intended. Solubility modulators may be mixed
with the beneficial agent prior to its combination with the viscous gel
or may be added to the viscous gel prior to the addition of the
beneficial agent, as appropriate.

[0097] The terms "subject" and "patient" mean, with respect to the
administration of a composition of the invention, an animal or a human
being.

[0098] The term "thixotropic" is used in its conventional sense to refer
to a gel composition that can liquefy or at least exhibit a decrease in
apparent viscosity upon application of mechanical force such as shear
force. The extent of the reduction is in part a function of the shear
rate of the gel when subjected to the shearing force. When the shearing
force is removed, the viscosity of the thixotropic gel returns to a
viscosity at or near that which it displayed prior to being subjected to
the shearing force. Accordingly, a thixotropic gel may be subjected to a
shearing force when injected from a syringe which temporarily reduces its
viscosity during the injection process. When the injection process is
completed, the shearing force is removed and the gel returns very near to
its previous state.

[0099] "A thixotropic agent" as used herein is one that increases the
thixotropy of the composition in which it is contained, promoting shear
thinning and enabling use of reduced injection force.

[0100] The term "bioerodible" refers to a material that gradually
decomposes, dissolves, hydrolyzes and/or erodes in situ. Generally, the
"bioerodible" polymers herein are polymers that are hydrolyzable, and
bioerode in situ primarily through hydrolysis.

[0101] The term "low molecular weight (LMW) polymer" refers to bioerodible
polymers having a weight average molecular weight ranging from about 3000
to about 10,000; preferably from about 3000 to about 9,000; more
preferably from about 4000 to about 8,000; and more preferably the low
molecular weight polymer has a molecular weight of about 7000, about
6000, about 5000, about 4000 and about 3000 as determined by gel
permeation chromatography (GPC).

[0102] The term "medium molecular weight (MMW) polymer" refers to
biocompatible, bioerodible polymers having a weight average molecular
weight ranging from between about 10,000 to about 30,000; preferably from
about 12,000 to about 20,000; more preferably from about 14,000 to about
18,000; and more preferably the medium molecular weight polymer has a
molecular weight of about 14,000, about 15,000, about 16,000, about
17,000 and about 18,000 as determined by gel permeation chromatography
(GPC). In preferred embodiments, a MMW polymer is selected from PLGA
RG502, PLGA RG752, and PLA R202.

[0103] The term "high molecular weight (HMW) polymer" refers to
biocompatible, bioerodible polymers having a weight average molecular
weight of greater than 30,000; preferably from about 30,000 to about
250,000; more preferably from about 30,000 to about 120,000 as determined
by gel permeation chromatography (GPC). In preferred embodiments, a HMW
polymer is selected from RG503, PLGA RG 755, PLA R206, PCL/PLA 75:25 and
PCL/PLA 25:75.

[0104] Since all solvents, at least on a molecular level, will be soluble
in water (i.e., miscible with water) to some very limited extent, the
term "immiscible" as used herein means that 7% or less by weight,
preferably 5% or less, of the solvent is soluble in or miscible with
water. For the purposes of this disclosure, solubility values of solvent
in water are considered to be determined at 25.degree. C. Since it is
generally recognized that solubility values as reported may not always be
conducted at the same conditions, solubility limits recited herein as
percent by weight miscible or soluble with water as part of a range or
upper limit may not be absolute. For example, if the upper limit on
solvent solubility in water is recited herein as "7% by weight," and no
further limitations on the solvent are provided, the solvent "triacetin,"
which has a reported solubility in water of 7.17 grams in 100 ml of
water, is considered to be included within the limit of 7%. A solubility
limit in water of less than 7% by weight as used herein does not include
the solvent triacetin or solvents having solubilities in water equal to
or greater than triacetin.

[0105] The following definitions apply to the molecular structures
described herein: As used herein, the phrase "having the formula" or
"having the structure" is not intended to be limiting and is used in the
same way that the term "comprising" is commonly used.

[0106] The term "alkyl" as used herein refers to a saturated hydrocarbon
group typically although not necessarily containing 1 to about 30 carbon
atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as
cyclopentyl, cyclohexyl and the like. Generally, although again not
necessarily, alkyl groups herein contain 1 to about 12 carbon atoms. The
term "lower alkyl" intends an alkyl group of 1 to 6 carbon atoms,
preferably 1 to 4 carbon atoms. "Substituted alkyl" refers to alkyl
substituted with one or more substituent groups, and the terms
"heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in which
at least one carbon atom is replaced with a heteroatom. If not otherwise
indicated, the terms "alkyl" and "lower alkyl" include linear, branched,
cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or
lower alkyl.

[0107] The term "aryl" as used herein, and unless otherwise specified,
refers to an aromatic substituent containing a single aromatic ring or
multiple aromatic rings that are fused together, linked covalently, or
linked to a common group such as a methylene or ethylene moiety.
Preferred aryl groups contain one aromatic ring or two fused or linked
aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether,
diphenylamine, benzophenone, and the like, and most preferred aryl groups
are monocyclic. "Substituted aryl" refers to an aryl moiety substituted
with one or more substituent groups, and the terms "heteroatom-containing
aryl" and "heteroaryl" refer to aryl in which at least one carbon atom is
replaced with a heteroatom. Unless otherwise indicated, the term "aryl"
includes heteroaryl, substituted aryl, and substituted heteroaryl groups.

[0108] The term "aralkyl" refers to an alkyl group substituted with an
aryl group, wherein alkyl and aryl are as defined above. The term
"heteroaralkyl" refers to an alkyl group substituted with a heteroaryl
group. Unless otherwise indicated, the term "aralkyl" includes
heteroaralkyl and substituted aralkyl groups as well as unsubstituted
aralkyl groups. Generally, the term "aralkyl" herein refers to an
aryl-substituted lower alkyl group, preferably a phenyl substituted lower
alkyl group such as benzyl, phenethyl, 1-phenylpropyl, 2-phenylpropyl,
and the like.

[0109] The term "heteroatom-containing" as in a "heteroatom-containing
hydrocarbyl group" refers to a molecule or molecular fragment in which
one or more carbon atoms is replaced with an atom other than carbon,
e.g., nitrogen, oxygen, sulfur, phosphorus or silicon. Similarly, the
term "heterocyclic" refers to a cyclic substituent that is
heteroatom-containing, the term "heteroaryl" refers to an aryl
substituent that is heteroatom-containing, and the like.

[0110] By "substituted" as in "substituted alkyl," "substituted aryl" and
the like, as alluded to in some of the aforementioned definitions, is
meant that in the alkyl or aryl moiety, respectively, at least one
hydrogen atom bound to a carbon atom is replaced with one or more
non-interfering substituents such as hydroxyl, alkoxy, thio, amino, halo,
and the like.

[0111] I. Injectable Depot Compositions:

[0112] As described previously, injectable depot compositions for delivery
of beneficial agents over a prolonged period of time may be formed as
viscous gels prior to injection of the depot into a subject. The viscous
gel supports dispersed beneficial agent to provide appropriate delivery
profiles, which include those having low initial burst, of the beneficial
agent as the beneficial agent is released from the depot over time.

[0113] The polymer, solvent and other agents of the invention must be
biocompatible; that is they must not cause irritation or necrosis in the
environment of use. The environment of use is a fluid environment and may
comprise a subcutaneous, intramuscular, intravascular (high/low flow),
intramyocardial, adventitial, intratumoral, or intracerebral portion,
wound sites, tight joint spaces or body cavity of a human or animal. In
certain embodiments, the beneficial agent may be administered locally to
avoid or minimize systemic side effects. Gels of the present invention
containing a beneficial agent may be injected/implanted directly into or
applied as a coating to the desired location, e.g., subcutaneous,
intramuscular, intravascular, intramyocardial, adventitial, intratumoral,
or intracerebral portion, wound sites, tight joint spaces or body cavity
of a human or animal.

[0114] Typically, the viscous gel will be injected from a standard
hypodermic syringe through a needle, a catheter, or a trocar, that has
been pre-filled with the beneficial agent-viscous gel composition to form
the depot. It is often preferred that injections take place using the
smallest size needle (i.e., smallest diameter) to reduce discomfort to
the subject when the injection is in a subcutaneous, intramuscular,
intravascular (high/low flow), intramyocardial, adventitial,
intratumoral, or intracerebral portion, wound sites, tight joint spaces
or body cavity of a human or animal. It is desirable to be able to inject
gels through a needle or a catheter ranging from 16 gauge and higher,
preferably 20 gauge and higher, more preferably 22 gauge and higher, even
more preferably 24 gauge and higher. With highly viscous gels, i.e., gels
having a viscosity of about 200 poise or greater, injection forces to
dispense the gel from a syringe having a needle in the 20-30 gauge range
may be so high as to make the injection difficult or reasonably
impossible when done manually. At the same time, the high viscosity of
the gel is desirable to maintain the integrity of the depot after
injection and during the dispensing period and also facilitate desired
suspension characteristics of the beneficial agent in the gel.

[0115] A. The Bioerodible, Biocompatible Polymer:

[0116] Polymers that are useful in conjunction with the methods and
compositions of the invention are bioerodible, i.e., they gradually
degrade e.g., enzymatically or hydrolyze, dissolve, physically erode, or
otherwise disintegrate within the aqueous fluids of a patient's body.
Generally, the polymers bioerode as a result of hydrolysis or physical
erosion, although the primary bioerosion process is typically hydrolysis
or enzymatic degradation.

[0118] It has been surprisingly found that the release rate of the
beneficial agent from the injectable depot gel formulations of the
invention can be varied by varying the polymer properties, such as the
type of polymer, the molecular weight of the polymer (including the modal
distribution of the polymer), and the comonomer ratio of the monomers
forming the polymer; the end group of the polymers; the type of solvent;
and by varying the polymer/solvent ratios to provide a controlled,
sustained release of a beneficial agent over a prolonged duration of time
equal to or greater than two weeks and up to one year after
administration, preferably over a period equal to or greater than one
month after administration; preferably over a period equal to or greater
than 2 months after administration, preferably over a period equal to or
greater than 3 months after administration, preferably over a period of
about 3 months to about 9 months after administration, preferably over a
period of about 3 months to about 6months after administration,
preferably over a period of up to about 3 months, up to about 4 months,
up to about 5 months; and up to about 6 months after administration. The
release rate profile and duration can be controlled by the appropriate
choice of a polymer (including the ratio of the monomers, e.g. L/G, CL/L
ratios), the molecular weight of the polymer (LMW, MMW, HMW), the end
group of the polymer (acid, ester); a water immiscible solvent, the
polymer/solvent ratio, emulsifying agent, pore former, solubility
modifier for the beneficial agent, an osmotic agent, and the like.

[0119] In another aspect, the present invention provides a method of
regulating the release of a beneficial agent from an injectable depot
composition. The duration and the rate of release of the beneficial agent
(e.g. burst index and release rate profile) are controlled by the
appropriate choice of the biodegradable polymer, the molecular weight of
the polymer, the comonomer ratio of the various monomers forming the
polymer (e.g., the L/G or CL/L ratio for a lactic acid-based polymer),
and the polymer/solvent ratios as tabulated in Tables A, B, C and D
below. Previously described injectable depot formulations having
polylactic acid (i.e. a L/G ratio of 100:0) exhibit a release profile of
the beneficial agent over a duration of about 3 months (which is. shorter
than the comparable depot composition of the instant invention, see e.g.,
Examples 20 and 21, and FIGS. 13, 16 and 17 as described in greater
detail hereinafter). As illustrated in the Examples below, it has been
discovered that PLGA depot gel compositions of the invention having a L/G
ratio of about 75:25 release the beneficial agent in a sustained manner
over a period of approximately 3-4 months. In additional embodiments,
PLGA depot gel compositions of the invention having a L/G ratio of about
100:0 (i.e. polylactic acid (PLA)) and a P/S ratio of about 55:45 to
about 65:35, release the beneficial agent in a sustained manner over a
period of approximately 6-8 months. In additional embodiments, PLGA depot
gel compositions of the invention having a molecular weight of about
14,000 to about 22,000; a L/G ratio of about 75:25 to about 100:0 and a
P/S ratio of about 50:50 to about 65:35, release the beneficial agent in
a sustained manner over a period of approximately 3-8 months.

[0120] In one aspect, duration and the rate of release (e.g., release rate
profile and burst index) of the beneficial agent are controlled by the
appropriate choice of the biodegradable polymer.

[0121] (A) Molecular Weight of the Polymer:

[0122] The molecular weight of polymer can be varied to regulate the
release rate profile and/or delivery duration of the beneficial agent. In
general, as the molecular weight of the polymer increases, one or more of
the following occurs: the burst index is lower, release rate profile is
flatter and/or duration of delivery is longer.

[0123] (B) Polymers with Different End Groups:

[0124] Depot gel compositions having a blend of polymers with different
end groups would result in a depot formulation having a lower burst index
than those polymers that are not blended and a regulated duration of
delivery. For example, blending PLGA RG502H (acid end group) with PLGA
RG502 (ester end group) lowers the burst index for a depot gel
composition having a one month duration of delivery; blending PLGA RG752H
with PLGA RG752 lowers the burst index for a depot gel composition having
a duration of delivery of about 3 months to about 4 months; blending PLA
R202H with PLA R202 lowers the burst index for a depot gel composition
having duration of delivery greater than or equal to 6 months; blending
PLGA RG502H and PLGA RG752 with PLA R202 lowers the burst index for a
depot gel composition having duration of delivery greater than or equal
to 6 months. In accordance with the invention, the depot gel compositions
comprise a blend of polymers, i.e. a blend of polymer components, and
preferably, the blend of polymers includes at least one lactic acid-based
polymer as one of the polymer components of the depot gel composition.

[0125] (C) Comonomer Ratio of the Polymer:

[0126] Varying the comonomer ratio of the various monomers forming the
polymer (e.g., the L/G or CL/L ratio for a given polymer), would result
in depot gel compositions having a lower burst index and a regulated
duration of delivery. For example, a depot gel composition having a
polymer with a L/G ratio of 50:50 has a short duration of delivery
ranging from 2 days to about one month; a depot gel composition having a
polymer with a L/G ratio of 65:35 has a duration of delivery of about 2
months; a depot gel composition having a polymer with a L/G ratio of
75:25 or L/CL ratio of 75:25 has a duration of delivery of about 3 months
to about 4 months; a depot gel composition having a polymer with a L/G
ratio of 85:15 has a duration of delivery of about 5 months; and a depot
gel composition having a polymer with a PLA or L/CL ratio of 25:75 has a
duration of delivery greater than or equal to 6 months.

[0127] (D) Polymers with Different Degradation Characteristics:

[0128] Depot gel compositions having a blend of a faster degrading polymer
with a slower degrading polymer would result in a depot formulation
having a lower burst index and a longer duration of delivery. For
example, blending PLGA RG 502 with PLGA RG752 would yield a depot gel
composition having a lower burst index (as compared to a gel composition
having PLGA RG752 alone) and duration of delivery of about 3 months to
about 4 months after administration. Blending PLGA RG502 and PLGA RG752
with PLA R202 would yield a depot gel composition having a lower burst
index (as compared to a gel composition having PLA 202 alone) and a
duration of delivery greater than or equal to 6 months after
administration.

[0129] (E) Polymers with Different Molecular Weight, End Group and
Comonomer Ratios:

[0130] Depot gel compositions having a blend of polymers having different
molecular weight, end group and comonomer ratios result in a depot
formulation having a lower burst index and a regulated duration of
delivery. For example, blending LMW PLGA (L/G: 50/50) and PLGA RG502H
(acid end group) with PLGA RG502 (ester end group) would yield a depot
gel composition having a lower burst index (as compared to a gel
composition having PLGA RG502 alone) and a duration of delivery of about
one month. Blending LMW PLGA (L/G: 50/50) and PLGA RG503H (acid end
group) with PLGA RG752 (ester end group) would yield a depot gel
composition having a lower burst index (as compared to a gel composition
having PLGA RG752 alone) and a duration of delivery of about 3 months to
about 4 months after administration. Blending LMW PLGA (L/G: 50/50) and
PLGA RG755H (acid end group) with PLA R202 (ester end group) would yield
a depot gel composition having a lower burst index (as compared to a gel
composition having PLA 202 alone) and a duration of delivery greater than
or equal to 6 after administration. Blending PLGA RG502H (acid end group)
and PLGA RG752 (ester end group) with PLA R206 (ester end group) would
yield a depot gel composition having a lower burst index (as compared to
a gel composition having PLA 202 alone) and a duration of delivery
greater than or equal to 6 after administration.

[0131] In another aspect, duration and the rate of release of the
beneficial agent are controlled by varying the polymer/solvent (P/S)
ratio. The polymer/solvent ratio of the depot gel composition can be
varied to regulate the release rate profile and/or delivery duration of
the beneficial agent. In general, the higher the P/S ratio, the lower the
burst index or flatter release rate profile.

[0135] The bioerodible polymers are selected from the group consisting of
low molecular weight (LMW) polymers, medium molecular weight (MMW)
polymers and high molecular weight (HMW) polymers. The low molecular
weight (LMW) bioerodible polymers have weight average molecular weight
ranging from about 3000 to about 10,000; preferably from about 3000 to
about 9,000; more preferably from about 4000 to about 8,000; and more
preferably the low molecular weight polymer has a molecular weight of
about 7000, about 6000, about 5000, about 4000 and about 3000 as
determined by gel permeation chromatography (GPC).

[0136] The medium molecular weight (MMW) bioerodible polymers have weight
average molecular weight ranging from between about 10,000 to about
30,000; preferably from about 12,000 to about 20,000; more preferably
from about 14,000 to about 18,000; and more preferably the medium
molecular weight polymer has a molecular weight of about 14,000, about
15,000, about 16,000, about 17,000 and about 18,000 as determined by gel
permeation chromatography (GPC). In preferred embodiments, a MMW polymer
is selected from PLGA RG502, PLGA RG752, and PLA R202.

[0137] The high molecular weight (HMW) bioerodible polymers have weight
average molecular weight of greater than 30,000; preferably from about
30,000 to about 250,000; more preferably from about 30,000 to about
120,000 as determined by gel permeation chromatography (GPC). In
preferred embodiments, a HMW polymer is selected from RG503, PLGA RG 755,
PLA R206, PCL/PLA 75:25 and PCL/PLA 25:75.

[0138] Preferably, the polymer matrix comprises about 0 wt % to about 95
wt % of low molecular weight (LMW) polymer, preferably about 20 wt % to
about 90 wt % of low molecular weight (LMW) polymer, more preferably
about 30 wt % to about 80 wt % of low molecular weight (LMW) polymer, and
more preferably about 40 wt % to about 75 wt % of low molecular weight
(LMW) polymer; about 0 wt % to about 50 wt % of high molecular weight
(HMW) polymer, preferably about 5 wt % to about 40 wt % of high molecular
weight (HMW) polymer, more preferably about 10 wt % to about 30 wt % of
high molecular weight (HMW) polymer, and more preferably about 15 wt % to
about 25 wt % of high molecular weight (HMW) polymer; and about 0 wt % to
about 95 wt % of medium molecular weight (MMW) polymer, preferably about
20 wt % to about 90 wt % of medium molecular weight (MMW) polymer, more
preferably about 30 wt % to about 80 wt % of medium molecular weight
(MMW) polymer, and more preferably about 40 wt % to about 65 wt % of
medium molecular weight (MMW) polymer.

[0139] Presently preferred polymers are polylactides, that is, a lactic
acid-based polymer that can be based solely on lactic acid or can be a
copolymer based on lactic acid, glycolic acid and/or caprolactone-based
polymers including caprolactone (CL), which may include small amounts of
other comonomers that do not substantially affect the advantageous
results, which can be achieved in accordance with the present invention.
As used herein, the term "lactic acid" includes the isomers L-lactic
acid, D-lactic acid, DL-lactic acid and lactide while the term "glycolic
acid" includes glycolide. Most preferred are polymers selected from the
group consisting of polylactide polymers, commonly referred to as PLA,
poly(lactide-co-glycolide)copolymers, commonly referred to as PLGA, and
poly(caprolactone-co-lactic acid) (PCL-co-LA). The polymer may have a
monomer ratio of lactic acid/glycolic acid (L/G) of from about 50:50 to
about 100:0, preferably from about 60:40 to about 85:15, preferably from
about 65:35 to about 75:25. In certain embodiments, when the desired
duration of release of the beneficial agent is about one month,
preferably the polymer has a L/G ratio of 50:50. In alternative
embodiments, when the desired duration of release of the beneficial agent
is about 2 months, preferably the polymer has a L/G ratio of 65:35; when
the desired duration of release of the beneficial agent is about 3
months, preferably the polymer has a L/G ratio of 75:25; and when the
desired duration of release of the beneficial agent is about 6 months,
preferably the polymer has a L/G ratio ranging from about 85:15 to about
100:0.

[0140] The poly(caprolactone-co-lactic acid) (PCL-co-LA) polymer has a
comonomer ratio of caprolactone/lactic acid (CL/L) of from about 10:90 to
about 90:10, from about 50:50; preferably from about 35:65 to about
65:35; and more preferably from about 25:75 to about 75:25. In certain
embodiments, the lactic acid based polymer comprises a blend of about
0-90% caprolactone, about 0-100% lactic acid, and about 0-60% glycolic
acid.

[0141] As indicated in aforementioned U.S. Pat. No. 5,242,910, the polymer
can be prepared in accordance with the teachings of U.S. Pat. No.
4,443,340. Alternatively, the lactic acid-based polymer can be prepared
directly from lactic acid or a mixture of lactic acid and glycolic acid
(with or without a further comonomer) in accordance with the techniques
set forth in U.S. Pat. No. 5,310,865. The contents of all of these
patents are incorporated by reference. Suitable lactic acid-based
polymers are available commercially. The lactic acid-based polymer may be
a low molecular weight polymer (LMW); a medium molecular weight polymer
(MMW) or a high molecular weight (HMW) or a combination thereof.

[0143] The biocompatible polymer is present in the gel composition in an
amount ranging from about 5 to about 90% by weight, preferably from about
20 to about 80% by weight, preferably from about 30 to about 75% by
weight, often about 35 to about 70% by weight of the viscous gel, and
about 40 to about 65% by weight the viscous gel comprising the combined
amounts of the biocompatible polymer and the solvent. The biodegradable,
biocompatible lactic acid-based polymer is in an amount comprising about
5wt. % to about 90 wt. %, and preferably from about 25 wt. % to about 80
wt. %, and more preferably from about 35 wt. % to about 75 wt. %. The
solvent will be added to polymer in amounts described below, to provide
injectable depot gel compositions.

[0144] B. Solvents:

[0145] The injectable depot composition of the invention contains a
water-immiscible solvent in addition to the bioerodible polymer and the
beneficial agent. In preferred embodiments, the compositions described
herein are also free of solvents having a miscibility in water that is
greater than 7 wt. % at 25.degree. C.

[0146] The solvent must be biocompatible, should form a viscous gel with
the polymer, and restrict water uptake into the implant. The solvent may
be a single solvent or a mixture of solvents exhibiting the foregoing
properties. The term "solvent", unless specifically indicated otherwise,
means a single solvent or a mixture of solvents. Suitable solvents will
substantially restrict the uptake of water by the implant and may be
characterized as immiscible in water, i.e., having a solubility in water
of less than 7% by weight. Preferably, the solvents are five weight
percent or less soluble in water; more preferably three weight percent or
less soluble in water; and even more preferably one weight percent or
less soluble in water. Most preferably the solubility of the solvent in
water is equal to or less than 0.5 weight percent.

[0147] Water miscibility may be determined experimentally as follows:
Water (1-5 g) is placed in a tared clear container at a controlled
temperature, about 20.degree. C., and weighed, and a candidate solvent is
added dropwise. The solution is swirled to observe phase separation. When
the saturation point appears to be reached, as determined by observation
of phase separation, the solution is allowed to stand overnight and is
re-checked the following day. If the solution is still saturated, as
determined by observation of phase separation, then the percent (w/w) of
solvent added is determined. Otherwise more solvent is added and the
process repeated. Solubility or miscibility is determined by dividing the
total weight of solvent added by the final weight of the solvent/water
mixture. When solvent mixtures are used, for example 20% triacetin and
80% benzyl benzoate, they are pre-mixed prior to adding to the water.

[0148] Solvents useful in this invention are generally less than 7% water
soluble by weight as described above. Solvents having the above
solubility parameter may be selected from aromatic alcohols, the lower
alkyl and aralkyl esters of aryl acids such as benzoic acid, the phthalic
acids, salicylic acid, lower alkyl esters of citric acid, such as
triethyl citrate and tributyl citrate and the like, and aryl, aralkyl and
lower alkyl ketones. Among preferred solvents are those having
solubilities within the foregoing range selected from compounds having
the following structural formulas (I), (II) and (III).

[0149] The aromatic alcohol has the structural formula (I)

Ar-(L)n-OH (I)

[0150] wherein Ar is a substituted or unsubstituted aryl or heteroaryl
group, n is zero or 1, and L is a linking moiety. Preferably, Ar is a
monocyclic aryl or heteroaryl group, optionally substituted with one or
more noninterfering substituents such as hydroxyl, alkoxy, thio, amino,
halo, and the like. More preferably, Ar is an unsubstituted 5- or
6-membered aryl or heteroaryl group such as phenyl, cyclopentadienyl,
pyridinyl, pyrimadinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl,
furanyl, thiophenyl, thiazolyl, isothiazolyl, or the like. The subscript
"n" is zero or 1, meaning that the linking moiety L may or may not be
present. Preferably, n is 1 and L is generally a lower alkylene linkage
such as methylene or ethylene, wherein the linkage may include
heteroatoms such as O, N or S. Most preferably, Ar is phenyl, n is 1, and
L is methylene, such that the aromatic alcohol is benzyl alcohol.

[0151] The aromatic acid ester or ketone may be selected from the lower
alkyl and aralkyl esters of aromatic acids, and aryl and aralkyl ketones.
Generally, although not necessarily, the aromatic acid esters and ketones
will respectively have the structural formula (II) or (III) 1

[0152] In the ester of formula (II), R1 is substituted or unsubstituted
aryl, aralkyl, heteroaryl or heteroaralkyl, preferably substituted or
unsubstituted aryl or heteroaryl, more preferably monocyclic or bicyclic
aryl or heteroaryl optionally substituted with one or more
non-interfering substituents such as hydroxyl, carboxyl, alkoxy, thio,
amino, halo, and the like, still more preferably 5- or 6-membered aryl or
heteroaryl such as phenyl, cyclopentadienyl, pyridinyl, pyrimadinyl,
pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl,
thiazolyl, or isothiazolyl, and most preferably 5- or 6-membered aryl. R2
is hydrocarbyl or heteroatom-substituted hydrocarbyl typically lower
alkyl or substituted or unsubstituted aryl, aralkyl, heteroaryl or
heteroaralkyl, preferably lower alkyl or substituted or unsubstituted
aralkyl or heteroaralkyl, more preferably lower alkyl or monocyclic or
bicyclic aralkyl or heteroaralkyl optionally substituted with one or more
non-interfering substituents such as hydroxyl, carboxyl, alkoxy, thio,
amino, halo, and the like, still more preferably lower alkyl or 5- or
6-membered aralkyl or heteroaralkyl, and most preferably lower alkyl or
5- or 6-membered aryl optionally substituted with one or more additional
ester groups having the structure --O--(CO)--R1. Most preferred esters
are benzoic acid and phthalic acid derivatives.

[0153] In the ketone of formula (III), R3 and R4 may be selected from any
of the R1 and R2 groups identified above.

[0156] Many of the solvents useful in the invention are available
commercially (Aldrich Chemicals, Sigma Chemicals) or may be prepared by
conventional esterification of the respective arylalkanoic acids using
acid halides, and optionally esterification catalysts, such as described
in U.S. Pat. No. 5,556,905, which is incorporated herein by reference,
and in the case of ketones, oxidation of their respective secondary
alcohol precursors.

[0158] The composition may also include, in addition to the
water-immiscible solvent(s), one or more additional miscible solvents
("component solvents"), provided that any such additional solvent is
other than a lower alkanol. Component solvents compatible and miscible
with the primary solvent(s) may have a higher miscibility with water and
the resulting mixtures may still exhibit significant restriction of water
uptake into the implant. Such mixtures will be referred to as "component
solvent mixtures." Useful component solvent mixtures may exhibit
solubilities in water greater than the primary solvents themselves,
typically between 0.1 weight percent and up to and including 50 weight
percent, preferably up to and including 30 weight percent, and most
preferably up to an including 10 weight percent, without detrimentally
affecting the restriction of water uptake exhibited by the implants of
the invention.

[0160] Preferred solvent mixtures are those in which benzyl benzoate is
the primary solvent, and mixtures formed of benzyl benzoate and either
triacetin, tributyl citrate, triethyl citrate or N-methyl-2-pyrrolidone,
or glycofurol. Preferred mixtures are those in which benzyl benzoate is
present by weight in an amount of 50% or more, more preferably 60% or
more and most preferably 80% or more of the total amount of solvent
present. Especially preferred mixtures are those of 80:20 mixtures by
weight of benzyl benzoate/triacetin and benzyl benzoate/N-methyl-2-pyrrol-
idone. In additional embodiments, the preferred solvent is benzyl alcohol,
and mixtures formed of benzyl alcohol and either benzyl benzoate or ethyl
benzoate. Preferred mixtures of benzyl alcohol/benzyl benzoate and benzyl
alcohol/ethyl benzoate are 1/99 mixtures by weight; 20/80 mixtures by
weight; 30/70 mixtures by weight; 50/50 mixtures by weight; 70/30
mixtures by weight; 80/20 mixtures by weight; 99/1 mixtures by weight.
Especially preferred mixtures of benzyl alcohol/benzyl benzoate and
benzyl alcohol/ethyl benzoate are 25/75 mixtures by weight and 75/25
mixtures by weight.

[0161] The solvent or solvent mixture is typically present in an amount of
from about 95 to about 10% by weight, preferably from about 80 to about
20% by weight, preferably from about 70-25% by weight, preferably about
65-30% by weight and often 60-40% by weight of the viscous gel, i.e., the
combined amounts of the polymer and the solvent. The polymer to solvent
ratio ranges from about 20:80 to about 90:10 by weight; preferably about
30:70 to about 80:20 by weight; preferably about 40:60 to about 75:25 by
weight; and more preferably about 45:55 to about 65:35 by weight.

[0162] In an especially preferred embodiment, the primary solvent is
selected from an aromatic alcohol and lower alkyl and aralkyl esters of
benzoic acid and the polymer is a lactic-acid based polymer, most
preferably selected from polylactide polymers (PLA),
poly(lactide-co-glycolide) copolymers (PLGA), and poly(caprolactone-co-la-
ctic acid) (PCL-co-LA) having a comonomer L/G ratio of about 50:50 to
about 100:0 and an L/CL ratio of about 25:75 to about 75:25; and a
polymer solvent ratio of about 40:60 to about 65:35. Preferably the
polymer has a weight average molecular weight ranging from about 3,000 to
about 120,000; preferably from about 7,000 to about 100,000; more
preferably from about 10,000 to about 80,000; and more preferably the
polymer has a molecular weight of about 14,000, about 16,000, about
20,000, about 30,000 and about 60,000. Presently, the most preferred
solvents are benzyl alcohol, benzyl benzoate and the lower alkyl esters
of benzoic acid, e.g. ethyl benzoate. The primary solvents, e.g.,
aromatic alcohol and benzoic acid esters may be used alone or in a
mixture with other miscible solvents, e.g., triacetin, or thixotropic
agents, e.g. ethanol, as described herein.

[0163] The solvent or solvent mixture is capable of dissolving the polymer
to form a viscous gel that can maintain particles of the beneficial agent
dissolved or dispersed and isolated from the environment of use prior to
release. The compositions of the present invention provide implants
useful both for systemic and local administration of beneficial agent,
the implants having a low burst index. Water uptake is controlled by the
use of a solvent or component solvent mixture that solublizes or
plasticizes the polymer but substantially restricts uptake of water into
implant. Additionally, the preferred compositions may provide viscous
gels that have a glass transition temperature that is less than
37.degree. C., such that the gel remains non-rigid for a period of time
after implantation of 24 hours or more.

[0164] The importance of restriction of water uptake and the appropriate
choice of a polymer and a water immiscible solvent for a controlled,
sustained delivery over a short duration can be appreciated by reference
to FIGS. 6-21 illustrating in vivo release rate profiles for various
compositions as a function of time.

[0165] In addition to the control of water uptake and associated initial
burst by choice of solvent, agents that modulate the water solubility of
the beneficial agent can also be utilized in conjunction with the
preferred solvents to control burst of beneficial agent from the implant.
Burst indices and percent of beneficial agent released in the first
twenty-four hours after implantation may be reduced by one-third to
two-thirds or more by the use of solubility modulators associated with
the beneficial agent. Such modulators are typically coatings, substances
that form complexes or otherwise associate with or stabilize the
beneficial agent such as metallic ions, other stabilizing agents, waxes,
lipids, oils, non-polar emulsions, and the like. Use of such solubility
modulators may permit the use of more highly water soluble solvents or
mixtures and achieve burst indices of 8 or less for systemic
applications, or with respect to local applications. Typically, the
implant systems useful in this invention will release, in the first 2
days after implantation, 60% or less of the total amount of beneficial
agent to be delivered to the subject from the implant system, preferably
50% or less, more preferably 40% or less and even more preferably 30% or
less.

[0166] Limited water uptake by the compositions of this invention can
often provide the opportunity to prepare compositions without solubility
modulators when in other compositions such modulators would be necessary.

[0167] In instances where the choice of solvent and polymer result in
compositions severely restricting water uptake by themselves, it may be
desirable to add osmotic agents or other agents and hydroattractants that
facilitate water uptake to desired levels. Such agents may be, for
example, sugars and the like, and are well known in the art.

[0168] Limited water uptake by the solvent-polymer compositions of the
present invention results in the implant compositions being formed
without the finger-like pores in the surface of implants formed using
prior art processes. Typically, a composition of the present invention
takes the form of a substantially, homogeneous, sponge-like gel, with the
pores in the interior of the implant being much the same as the pores on
the surface of the implant. Compositions of the present invention retain
their gel-like consistency and administer a beneficial agent in a
controlled manner, at a sustained rate over a short duration of time than
do prior art devices. This is possible with the appropriate choice of
polymers and water immiscible solvents, and further since the injectable
depot gel compositions of the present invention generally have a glass
transition temperature, Tg, of less than body temperature of the subject,
e.g. 37.degree. C. for humans. Because of the immiscibility of the
solvents that are useful in this invention with water, water uptake by
the implant is restricted and the pores that do form tend to resemble a
closed cell structure without significant numbers of larger pores or
pores extending from the surface into the interior of the implant being
open at the surface of the implant. Furthermore, the surface pores offer
only a limited opportunity for water from body fluids to enter the
implant immediately after implantation, thus controlling the burst
effect. Since the compositions often will be highly viscous prior to
implantation, when the composition is intended for implantation by
injection, the viscosity optionally may be modified by the use of
viscosity-reducing, miscible solvents or the use of emulsifiers, or by
heating to obtain a gel composition having a viscosity or shear
resistance low enough to permit passage of the gel composition through a
needle.

[0169] The limit on the amount of beneficial agent released in the first
24 hours that is either desired or required will depend on circumstances
such as the overall duration of the delivery period, the therapeutic
window for the beneficial agent, potential adverse consequences due to
overdosing, cost of beneficial agent, and the type of effect desired,
e.g., systemic or local. Preferably, 60% or less of the beneficial agent
will be released in the first 2 days after implantation, preferably 50%
or less, more preferably 40% or less and even more preferably 30% or
less, where the percentage is based on the total amount of beneficial
agent to be delivered over the duration of the delivery period.

[0170] Depending on the particular solvent or solvent mixture selected,
the polymer and beneficial agent, and optionally solubility modulators of
the beneficial agent, the compositions of the present invention intended
for systemic delivery may provide a gel composition having a burst index
of 8 or less, preferably 6 or less, more preferably 4 or less and most
preferably 2 or less. Compositions of PLGA weight average molecular
weight ranging from about 3,000 to about 120,000; preferably from about
7,000 to about 100,000; more preferably from about 10,000 to about
80,000; and more preferably the polymer has a molecular weight of about
14,000 to about 60,000, with solvents having a miscibility in water of
less than 7% by weight, optionally combined with the other solvents,
providing implants intended for systemic delivery of beneficial agent
having a burst index of 10 or less, preferably 7 or less, more preferably
5 or less and most preferably 3 or less, are particularly advantageous.
The use of solvent mixtures as discussed herein can be particularly
advantageous as a means of providing sufficient plasticizing of the
polymer to obtain viscous gel formation and at the same time meet the
desired burst indices and percentage release objectives of the
compositions of the invention.

[0171] Compositions intended for local delivery of beneficial agent are
formed in the same manner as those intended for systemic use. However,
because local delivery of beneficial agent to a subject will not result
in detectable plasma levels of beneficial agent, such systems have to be
characterized by percentage of beneficial agent released in a
predetermined initial period, rather than a burst index as defined
herein. Most typically, that period will be the first 24 hours after
implantation and the percentage will be equal to the amount by weight of
the beneficial agent released in the period (e.g. 24 hours) divided by
the amount by weight of the beneficial agent intended to be delivered in
the duration of the delivery period; multiplied by the number 100.
Compositions of the present invention will have initial bursts of 40% or
less, preferably 30% or less, most preferably 20% or less, for most
applications.

[0172] In many instances, it may be desirable to reduce the initial burst
of beneficial agent during local administration to prevent adverse
effects. For example, implants of the invention containing
chemotherapeutic agents are suitable for direct injection into tumors.
However, many chemotherapeutic agents may exhibit toxic side effects when
administered systemically. Consequently, local administration into the
tumor may be the treatment method of choice. It is necessary, however, to
avoid administration of a large burst of the chemotherapeutic agent if it
is possible that such agent would enter the vascular or lymphatic systems
where it may exhibit side affects. Accordingly, in such instances the
implantable systems of the present invention having limited burst as
described herein are advantageous.

[0173] The gel formed by mixing the polymer and the solvent typically
exhibits a viscosity of from about 100 to about 50,000 poise, preferably
from about 500 to about 30,000 poise, more preferably from about 500 to
about 10,000 poise measured at a 1.0 sec-1 shear rate and 25.degree. C.
using a Haake Rheometer at about 1-2 days after mixing is completed.
Mixing the polymer with the solvent can be achieved with conventional low
shear equipment such as a Ross double planetary mixer for from about 10
minutes to about 1 hour, although shorter and longer periods may be
chosen by one skilled in the art depending on the particular physical
characteristics of the composition being prepared. Since the depot gel
composition of the invention are administered as an injectable
composition, a countervailing consideration when forming depot gel
compositions that are viscous gels is that the polymer/solvent/beneficial
agent composition have sufficiently low viscosity in order to permit if
to be forced through a small diameter, e.g., 18-20 gauge needle. If
necessary, adjustment of viscosity of the gel for injection can be
accomplished with emulsifying agents as described herein. Yet, such
compositions should have adequate dimensional stability so as to remain
localized and be able to be removed if necessary. The particular gel or
gel-like compositions of the present invention satisfy such requirements.

[0174] If the polymer composition is to be administered as an injectable
gel, the level of polymer dissolution will need to be balanced with the
resulting gel viscosity, to permit a reasonable force to dispense the
viscous gel from a needle or a catheter, and the potential burst effect.
Highly viscous gels enable the beneficial agent to be delivered without
exhibiting a significant burst effect, but may make it difficult to
dispense the gel through a needle or a catheter. In those instances, an
emulsifying agent may optionally be added to the composition. Also, since
the viscosity may generally be lowered as the temperature of the
composition increases, it may be advantageous in certain applications to
reduce the viscosity of the gel by heating to provide a more readily
injectable composition. The shear thinning characteristics of the depot
gel compositions of the present invention allow them to be readily
injected into an animal including humans using standard gauge needles or
catheters without requiring undue dispensing pressure.

[0175] When the emulsifying agent is mixed with the viscous gel formed
from the polymer and the solvent using conventional static or mechanical
mixing devices, such as an orifice mixer, the emulsifying agent forms a
separate phase composed of dispersed droplets of microscopic size that
typically have an average diameter of less than about 100 microns. The
continuous phase is formed of the polymer and the solvent. The particles
of the beneficial agent may be dissolved or dispersed in either the
continuous phase or the droplet phase. In the resulting thixotropic
composition, the droplets of emulsifying agent elongate in the direction
of shear and substantially decrease the viscosity of the viscous gel
formed from the polymer and the solvent. For instance, with a viscous gel
having a viscosity of from about 5,000 to about 50,000 poise measured at
1.0 sec.sup.-1 at 25.degree. C., one can obtain a reduction in viscosity
to less than 100 poise when emulsified with a 10% ethanol/water solution
at 25.degree. C. as determined by Haake Rheometer.

[0176] When used, the emulsifying agent typically is present in an amount
ranging from about 5 to about 80%, preferably from about 20 to about 60%
and often 30 to 50% by weight based on the amount of the injectable depot
gel composition, that is the combined amounts of polymer, solvent,
emulsifying agent and beneficial agent. Emulsifying agents include, for
example, solvents that are not fully miscible with the polymer solvent or
solvent mixture. Illustrative emulsifying agents are water, alcohols,
polyols, esters, carboxylic acids, ketones, aldehydes and mixtures
thereof. Preferred emulsifying agents are alcohols, propylene glycol,
ethylene glycol, glycerol, water, and solutions and mixtures thereof.
Especially preferred are water, ethanol, and isopropyl alcohol and
solutions and mixtures thereof. The type of emulsifying agent affects the
size of the dispersed droplets. For instance, ethanol will provide
droplets that have average diameters that can be on the order of ten
times larger than the droplets obtained with an isotonic saline solution
containing 0.9% by weight of sodium chloride at 21.degree. C.

[0177] It is to be understood that the emulsifying agent does not
constitute a mere diluent that reduces viscosity by simply decreasing the
concentration of the components of the composition. The use of
conventional diluents can reduce viscosity, but can also cause the burst
effect mentioned previously when the diluted composition is injected. In
contrast, the injectable depot composition of the present invention can
be formulated to avoid the burst effect by selecting the appropriate
polymer, the solvent and emulsifying agent so that once injected into
place, the emulsifying agent has little impact on the release properties
of the original system.

[0178] Although the injectable depot gel composition of the present
invention preferably are formed as viscous gels, the means of
administration of the implants is not limited to injection, although that
mode of delivery may often be preferred. Where the injectable depot gel
composition will be administered as a leave-behind product, it may be
formed to fit into a body cavity existing after completion of surgery or
it may be applied as a flowable gel by brushing or palleting the gel onto
residual tissue or bone. Such applications may permit loading of
beneficial agent in the gel above concentrations typically present with
injectable compositions.

[0179] C. Beneficial Agents:

[0180] The beneficial agent can be any physiologically or
pharmacologically active substance or substances optionally in
combination with pharmaceutically acceptable carriers and additional
ingredients such as antioxidants, stabilizing agents, permeation
enhancers, etc. that do not substantially adversely affect the
advantageous results that can be attained by the present invention. The
beneficial agent may be any of the agents which are known to be delivered
to the body of a human or an animal and that are preferentially soluble
in water rather than in the polymer-dissolving solvent. These agents
include drug agents, medicaments, vitamins, nutrients, or the like.
Included among the types of agents which meet this description are lower
molecular weight compounds, proteins, peptides, genetic material,
nutrients, vitamins, food supplements, sex sterilants, fertility
inhibitors and fertility promoters.

[0183] The present invention also finds application with chemotherapeutic
agents for the local application of such agents to avoid or minimize
systemic side effects. Gels of the present invention containing
chemotherapeutic agents may be injected directly into the tumor tissue
for sustained delivery of the chemotherapeutic agent over time. In some
cases, particularly after resection of the tumor, the gel may be
implanted directly into the resulting cavity or may be applied to the
remaining tissue as a coating. In cases in which the gel is implanted
after surgery, it is possible to utilize gels having higher viscosities
since they do not have to pass through a small diameter needle.
Representative chemotherapeutic agents that may be delivered in
accordance with the practice of the present invention include, for
example, carboplatin, cisplatin, paclitaxel, 5-fluorouracil, BCNU,
vincristine, camptothecin, etopside, cytokines, ribozymes, interferons,
oligonucleotides and oligonucleotide sequences that inhibit translation
or transcription of tumor genes, functional derivatives of the foregoing,
and generally known chemotherapeutic agents such as those described in
U.S. Pat. No. 5,651,986. The present application has particular utility
in the sustained delivery of water soluble chemotherapeutic agents, such
as for example cisplatin and carboplatin and the water soluble
derivatives of paclitaxel. Those characteristics of the invention that
minimize the burst effect are particularly advantageous in the
administration of water soluble beneficial agents of all kinds, but
particularly those compounds that are clinically useful and effective but
may have adverse side effects.

[0184] To the extent not mentioned above, the beneficial agents described
in aforementioned U.S. Pat. No. 5,242,910 can also be used. One
particular advantage of the present invention is that materials, such as
proteins, as exemplified by the enzyme lysozyme, and cDNA, and DNA
incorporated into vectors both viral and nonviral, which are difficult to
microencapsulate or process into microspheres can be incorporated into
the compositions of the present invention without the level of
degradation caused by exposure to high temperatures and denaturing
solvents often present in other processing techniques.

[0185] The beneficial agent is preferably incorporated into the viscous
gel formed from the polymer and the solvent in the form of particles
typically having an average particle size of from about 0.1 to about 250
microns, preferably from about 1 to about 125 microns and often from 10
to 90 microns. For instance, particles having an average particle size of
about 5 microns have been produced by spray drying or freeze drying an
aqueous mixture containing 50% sucrose and 50% chicken lysozyme (on a dry
weight basis) and mixtures of 10-20% hGH and 15-30 mM zinc acetate. Such
particles have been used in certain of the examples illustrated in the
figures. Conventional lyophilization processes can also be utilized to
form particles of beneficial agents of varying sizes using appropriate
freezing and drying cycles, followed by appropriate grounding and
sieving.

[0186] To form a suspension or dispersion of particles of the beneficial
agent in the viscous gel formed from the polymer and the solvent, any
conventional low shear device can be used such as a Ross double planetary
mixer at ambient conditions. In this manner, efficient distribution of
the beneficial agent can be achieved substantially without degrading the
beneficial agent.

[0187] The beneficial agent is typically dissolved or dispersed in the
composition in an amount of from about 0.1 to about 70% by weight,
preferably in an amount of from about 0.5 to about 50% and often 1 to 30%
by weight of the combined amounts of the polymer, solvent and beneficial
agent. Depending on the amount of beneficial agent present in the
composition, one can obtain different release profiles and burst indices.
More specifically, for a given polymer and solvent, by adjusting the
amount of these components and the amount of the beneficial agent, one
can obtain a release profile that depends more on the degradation of the
polymer than the diffusion of the beneficial agent from the composition
or vice versa. In general, during the early stages, the release rate
profile is generally controlled by the rate of diffusion and the rate of
dissolution of the beneficial agent from the composition; while in the
later stages, polymer degradation is the major factor in determining the
release rate profiles. In this respect, at lower beneficial agent loading
level, the release profile depends primarily on the rate of degradation
of the polymer, and secondarily on the diffusion of the beneficial agent
from the composition, wherein generally the release rate increases or is
constant (e.g., flat profile) with time.

[0188] At higher beneficial agent loading levels, the release rate depends
on the solubility of the beneficial agent in the depot gel composition or
surrounding medium. For example, if the beneficial agent has the high
solubility in the composition or surrounding medium, the release profile
depends primarily on the rate of diffusion of the beneficial agent from
the composition and secondarily on the rate of polymer degradation,
wherein generally, the release rate decreases with time. If the
beneficial agent has very low solubility in the composition or
surrounding medium, the release profile depends primarily on the rate of
diffusion and the rate of dissolution of the beneficial agent from the
composition, and secondarily on the rate of polymer degradation, wherein
generally the release rate is constant with time.

[0189] At intermediate beneficial agent loading levels, the release rate
depends on the combined effects of diffusion of the beneficial agent from
the composition and the rate of polymer degradation, wherein this
combined effect can be tailored to achieve a substantially constant
release rate profile. In order to minimize burst, loading of beneficial
agent on the order of 30% or less by weight of the overall gel
composition, i.e., polymer, solvent and beneficial agent, is preferred,
and loading of 20% or less is more preferred.

[0190] Release rates and loading of beneficial agent will be adjusted to
provide for therapeutically-effective delivery of the beneficial agent
over the intended sustained delivery period. Preferably, the beneficial
agent will be present in the polymer gel at concentrations that are above
the saturation concentration of beneficial agent in water to provide a
drug reservoir from which the beneficial agent is dispensed. While the
release rate of beneficial agent depends on the particular circumstances,
such as the beneficial agent to be administered, release rates on the
order of from about 0.1 to about 10000 micrograms/day, preferably from
about 1 to about 5000 micrograms per day, for periods of from about 2
weeks to about one year can be obtained. Greater amounts may be delivered
if delivery is to occur over shorter periods. Generally, higher release
rate is possible if a greater burst can be tolerated. In instances where
the gel composition is surgically implanted, or used as a "leave behind"
depot when surgery to treat the disease state or another condition is
concurrently conducted, it is possible to provide higher doses that would
normally be administered if the implant was injected. Further, the dose
of beneficial agent may be controlled by adjusting the volume of the gel
implanted or the injectable gel injected.

[0191] FIGS. 6 A-D and 7-21 illustrate representative release profiles of
various beneficial agents obtained in rats from preferred compositions of
this invention. As illustrated in the figures, the injectable depot gel
formulations of the invention comprising polymers provide a controlled,
sustained release of a beneficial agent over a specified/desired duration
of time. The duration and the release rate profiles can be adjusted
depending on the nature of the polymer and the properties of the polymer
(e.g. MW, comonomer ratios, end-group); the nature of the solvent and the
polymer/solvent ratio.

[0192] D. Optional Additional Components:

[0193] Other components may be present in the injectable depot gel
composition, to the extent they are desired or provide useful properties
to the composition, such as polyethylene glycol, hydroscopic agents,
stabilizing agents, pore forming agents, thixotropic agents and others.
When the composition includes a peptide or a protein that is soluble in
or unstable in an aqueous environment, it may be highly desirable to
include a solubility modulator that may, for example, be a stabilizing
agent, in the composition. Various modulating agents are described in
U.S. Pat. Nos. 5,654,010 and 5,656,297, which are incorporated herein by
reference. In the case of hGH, for example, it is preferable to include
an amount of a salt of a divalent metal, preferably zinc. Examples of
such modulators and stabilizing agents, which may form complexes with the
beneficial agent or associate to provide the stabilizing or modulated
release effect, include metal cations, preferably divalent, present in
the composition as magnesium carbonate, zinc carbonate, calcium
carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc
sulfate, zinc chloride, magnesium chloride, magnesium oxide, magnesium
hydroxide, other antacids, and the like. The amounts of such agents used
will depend on the nature of the complex formed, if any, or the nature of
the association between the beneficial agent and the agent. Molar ratios
of solubility modulator or stabilizing agent to beneficial agent of about
100:1 to 1:1, preferably 10:1 to 1:1, typically can be utilized.

[0194] The thixotropic agent, i.e. an agent that imparts thixotropic
properties to the polymer gel, is selected from the lower alkanols. Lower
alkanol means an alcohol that contains 2-6 carbon atoms and is straight
chain or branched chain. Such alcohols may be exemplified by ethanol,
isopropanol, and the like. Importantly, such a thixotropic agent is not a
polymer solvent. (See e.g., Development of an in situ forming
bidegradable poly-lactide-co-glycolide system for controlled release of
proteins, Lambert, W. J., and Peck, K. D., Journal of Controlled Release,
33 (1995) 189-195).

[0195] Pore forming agents include, biocompatible materials that when
contacted with body fluids dissolve, disperse or degrade to create pores
or channels in the polymer matrix. Typically, organic and non-organic
materials that are water soluble such as sugars (e.g., sucrose,
dextrose), water soluble salts (e.g., sodium chloride, sodium phosphate,
potassium chloride, and sodium carbonate), water soluble solvents such as
N-methyl-2-pyrrolidone and polyethylene glycol and water soluble polymers
(e.g., carboxmethylcellulose, hydroxypropylcellulose, and the like) can
conveniently be used as pore formers. Such materials may be present in
amounts varying from about 0.1% to about 100% of the weight of the
polymer, but will typically be less than 50% and more typically less than
10-20% of the weight of polymer.

[0196] II. Utility and Administration:

[0197] The means of administration of the depot gel compositions is not
limited to injection, although that mode of delivery may often be
preferred. Where the depot gel composition will be administered as a
leave-behind product, it may be formed to fit into a body cavity existing
after completion of surgery or it may be applied as a flowable gel by
brushing or palleting the gel onto residual tissue or bone. Such
applications may permit loading of beneficial agent in the gel above
concentrations typically present with injectable compositions.

[0198] Compositions of this invention without beneficial agent are useful
for wound healing, bone repair and other structural support purposes.

[0199] To further understand the various aspects of the present invention,
the results set forth in the previously described figures were obtained
in accordance with the following examples.

EXAMPLE 1

Depot Vehicle Preparation

[0200] A gel vehicle for use in an injectable depot of the composition was
prepared as follows. A glass vessel was tared on a Mettler AE 163
analytical balance or a Mettler PJ3000 top loader balance. Poly
(D,L-lactide-co-glycolide) (PLGA), (L/G ratio of 50/50) with an inherent
viscosity of 0.15 (PLGA-BPI, Birmingham Polymers, Inc., Birmingham,
Ala.); Resomer.RTM. PLGA RG502 (L/G ratio of 50/50), Resomer.RTM. PLGA
RG503 (L/G ratio of 50/50); 50:50 Resomer.RTM. RG504 (PLGARG 504); or a
Poly (D,L-lactide-co-glycolide) (PLGA) (L/G ratio of 75/25, Resomer.RTM.
RG752 (Boehringer Ingeheim Chemicals Inc., Petersburg, Va.), were milled
and sieved below 425 micron. The polymer was weighed into the glass
vessel. The glass vessel containing the polymer was tared and the
corresponding solvent was added. Amounts expressed as percentages for
various polymer/solvent combinations are set forth in Table 1, below. The
polymer/solvent mixture was stirred at 250.+-.50 rpm (IKA electric
stirrer, IKH-Werke GmbH and Co., Stanfen, Germany) for about 5-10
minutes, resulting in a sticky paste-like substance containing polymer
particles. The vessel, containing the polymer/solvent mixture was sealed
and placed in a temperature-controlled incubator equilibrated to
37.degree. C. for 1 to 4 days, with intermittent stirring, depending on
type and/or amount of solvent and polymer. The polymer/solvent mixture
was removed from the incubator when it appeared to be a clear amber
homogeneous solution. Thereafter, the mixture was placed in an oven
(65.degree. C., 30 minutes) until polymer was dissolved in the mixture.

[0205] Lyophilized particles were prepared from tris buffer solutions (5
or 50 mM: pH 7.6) containing hGH (5 mg/mL) using a Durastop .mu.P
Lyophilizer in accordance with the following freezing and drying cycles:

9
Freezing Ramp down at 2.5 C/min to -30.degree. C. and
hold for 30 min
cycle Ramp down at 2.5 C/min to -30.degree. C. and
hold for 30 min
Drying Ramp up at 0.5 C/min to 10.degree. C. and
hold for 960 min
cycle Ramp up at 0.5 C/min to 20.degree. C. and
hold for 480 min
Ramp up at 0.5 C/min to 25.degree. C. and hold
for 300 min
Ramp up at 0.5 C/min to 30.degree. C. and hold for
300 min
Ramp up at 0.5 C/min to 5.degree. C. and hold for 5000
min

EXAMPLE 3

HGH-Stearic Acid Particle Preparation

[0206] Human growth hormone (hGH) particles were prepared as follows:
Lyophilized hGH (3.22 grams, Pharmacia-Upjohn, Stockholm, Sweden) and
stearic acid (3.22 grams, 95% pure, Sigma-Aldrich Corporation, St. Louis,
Mo.) were blended and ground. The ground material was compressed in a 13
mm round die, with a force of 10,000 pounds for 5 minutes. Compressed
tablets were ground and sieved through a 70 mesh screen followed by a 400
mesh screen to obtain particles having a size range between 38-212
microns.

EXAMPLE 4

Bupivacaine Base Preparation

[0207] Bupivacaine hydrochloride (Sigma-Aldrich Corporation, St. Louis,
Mo.) was dissolved in de-ionized (DI) water at a concentration of 40
mg/ml (saturation). A calculated amount of sodium hydroxide (in the form
of 1 N solution) was added to the solution and the pH of the final
mixtures was adjusted to 10 to precipitate the Bupivacaine base. The
precipitated product was filtered, and further washed with DI water for
at least three times. The precipitated product was dried at ca.
40.degree. C. in vacuum for 24 h.

[0209] Bupivacaine particles were prepared as follows: Bupivacaine
hydrochloride (100 grams, Sigma-Aldrich Corporation, St. Louis, Mo.) was
grounded and sieved through 63-125 micron sieves. The bupivacaine
particles and stearic acid (100 grams, 95% pure, Sigma-Aldrich
Corporation, St. Louis, Mo.) were blended and ground. The ground material
was compressed in a 13 mm round die, with a force of 5,000 pounds for 5
minutes. Compressed tablets were ground and sieved through a 120 mesh
screen followed by a 230 mesh screen to obtain particles having a size
range between 63-125 microns.

[0211] Stearic acid (95% pure, Sigma-Aldrich Corporation, St. Louis, Mo.)
was passed through a 120-mesh screen (125 .mu.m). Equal amounts of milled
leuprolide acetate (<63 .mu.m, prepared as described in Example 2
above) and sieved stearic acid were transferred to the Waring blender and
blended for 30 seconds. The blended materials were compressed in a 13 mm
round die using compression force of 5000 lbs and hold time of 5 min.
Compressed pellets were ground and sieved through a 120-mesh (125 .mu.m)
sieve and retained on a 230 mesh (63 .mu.m) sieve.

[0213] Equal amount of Buprenorphine particles (prepared as described in
Example 4) above and stearic acid (prepared as described in Example 3)
were blended and ground. The ground material was compressed in a 13 mm
round die, with a force of 5,000 pounds for 5 minutes. Compressed tablets
were ground and sieved through a 120 mesh screen followed by a 230 mesh
screen to obtain particles having a size range between 63-125 microns.

EXAMPLE 11

Drug Loading

[0214] Compressed particles comprising beneficial agent with or without
stearic acid prepared as above were added to a gel vehicle in an amount
of 5-30% by weight and blended manually until the dry powder was wetted
completely. Then, the milky light yellow particle/gel mixture was
thoroughly blended by conventional mixing using a Caframo mechanical
stirrer with an attached square-tip metal spatula. Resulting formulations
are illustrated in Tables 4-12 below. Final homogenous gel formulations
were transferred to 3, 10 or 30 cc disposable syringes for storage or
dispensing.

[0223] In general, viscosity of the depot vehicle formulations was tested
using a Bohlin CVO 120 rheometer (Bohlin Instruments, Cranbury, N.J.).
All testing were performed at 24.degree. C. using 20 mm parallel plates.
The viscosity of various gel formulations or leuprolide acetate depot
formulations of the invention, as tabulated in Tables 6-12, was tested as
described above. As illustrated in FIGS. 1, 2 and 3 the depot
formulations (Formulations # 42-48, 51 and 52) have different rheological
properties. Thus, the depot formulations with wide range of viscosities
can be achieved by the combination of different polymers (PLGA type,
molecular weight etc.), solvent or co-solvent, different polymer/solvent
ratios according to the present invention.

EXAMPLE 13

Injection Force of Leuprolide Acetate Depot Formulations

[0224] The injection force of the depot vehicle formulations was tested on
an Instron tensile testing instrument (Instron, Canton, Mass.), where the
maximum force required to move the syringe plunger at a speed of 1
ml/minute was determined. The vehicle formulations were pre-filled into
Hamilton syringes prior to the Instron tests. All tests were conducted at
room temperature, using a 24-gauge 0.5 inch long needle.

[0225] The injection force of various gel formulations or leuprolide
acetate depot formulations of the invention, as tabulated in Tables 6-12,
was tested as described above. As illustrated in FIGS. 4 and 5, the depot
formulations (Formulations 42-45 and 48-50) have different injection
forces. Thus, depot formulations with different injection forces can be
tailored by the combination of different polymers (PLGA type, molecular
weight etc.), solvent or co-solvent, different polymer/solvent ratios
according to the present invention.

EXAMPLE 14

In Vitro Release Rate Profiles of Depot Gel Formulations

[0226] A representative number of implantable gels were prepared in
accordance with the foregoing procedures and tested for in vitro release
of beneficial agent as a function of time. In general, the in vitro
release of bioactive agent from the depot formulation of the present
invention was performed as follows. The depot gel formulation (80-120 mg)
was loaded into a tea bag and placed in a 20 mL scintillation vial and
the release medium (5 mL, phosphate buffer saline (PBS)+0.1% Tween 20, pH
7.4) was added to the vial. The vial was incubated in a 37.degree. C.
water bath with gentle agitation. The medium was replaced daily for the
first 5 days, then twice a week thereafter till the end of release
duration. The amount of bioactive agent released from the depot was
measured by various methods dependent the nature of the bioactive agent:
size exclusion chromatography high pressure liquid chromatography (SEC
HPLC) is generally used for protein, while reverse phase high pressure
liquid chromatography (rpHPLC) or ultraviolet (UV) techniques are
generally used for small molecular compounds.

EXAMPLE 15

In Vivo Release Rate Profiles of Depot Gel Formulations

[0227] A representative number of implantable gels were prepared in
accordance with the foregoing procedures and tested for in vivo studies
in rats to determine release of the beneficial agent as determined by
blood serum or plasma concentrations of beneficial agent as a function of
time.

[0228] In general, in vivo studies in rats were performed following an
open protocol to determine plasma levels of the beneficial agent (e.g.,
hGH, bupivicaine, leuprolide, buprenorphine) upon systemic administration
of the beneficial agent via the implant systems of this invention. Depot
gel formulations containing the beneficial agent (prepared as described
in the Examples above) were loaded into 0.25 cc or a 0.5 cc disposable
syringes (e.g. Hamilton Gastight syringes) or catheters. Disposable
needles (16 gauge or 18 gauge) were attached to the syringes and were
heated to 37.degree. C. using a circulator bath. The depot gel
formulations (as tabulated in Tables 1-12) were injected into rats and
blood was drawn at specified time intervals. All plasma samples were
stored at 4.degree. C. prior to analysis. Samples were analyzed for the
beneficial agent using any one of the following methods: radio immuno
assay (RIA) or validated LC/MS/MS method (Ricerca, LLC, Painesville,
Ohio).

EXAMPLE 16

hGH in Vivo Studies

[0229] A representative number of implantable gels as tabulated in Tables
4-6 were tested for in rats to determine vivo release rate profiles as
described in Example 15 above. In particular, depot gel hGH compositions
were injected from customized 0.5 cc disposable syringes having
disposable 16 gauge needles, into rats and blood was drawn at specified
time intervals. The release rate profile of hGH from various depot gel
formulations was determined by measuring the blood serum or plasma
concentrations of hGH as a function of time, as illustrated in FIGS. 6
A-D (formulations 21, 22, 29-31, and 33-40). Samples were analyzed for
intact hGH content using a radio immuno assay (RIA).

EXAMPLE 17

Bupivacaine in Vivo Studies

[0230] A representative number of implantable gels as tabulated in Table 4
were tested for in rats to determine vivo release rate profiles as
described in Example 15 above. In particular, depot gel bupivacaine
compositions were injected from customized 0.5 cc disposable syringes
having disposable 18 gauge needles, into rats and blood was drawn at
specified time intervals (1 hour, 4 hours and on days 1, 2, 5, 7, 9 and
14, 21 and 28) and analyzed for bupivacaine using LC/MS. FIGS. 7, 8 and 9
illustrate representative in vivo release profiles of bupivacaine
hydrochloride (formulations 17 and 18) and bupivacaine base (formulations
19 and 20) obtained in rats from various depot formulation including
those of the present invention. The in vivo release profile of the depot
formulations with low molecular weight PLGA (formulations 18 and 20 in
FIGS. 7, 8 and 9) exhibited a shorter release duration of approximately 7
days as compared to the control formulations (with higher molecular
weight PLGA, formulations 17 and 19).

EXAMPLE 18

Bupivacaine in Vivo Studies

[0231] A representative number of implantable gels as tabulated in Table
13 were tested for in rats to determine vivo release rate profiles as
described in Example 17 above. FIGS. 10 and 11 illustrate representative
in vivo release profiles of bupivacaine obtained in rats from various
depot formulation, including those of the present invention. As
illustrated in the figures, when the same amount of bupivacaine was
administrated, the duration of the in vivo sustained release of
bupivicaine from the formulation is directly proportional to the percent
loading of bupivacaine within the depot gel composition. In particular,
at 10% bupivicaine HCl loading, the amount of bupivicaine released
increased with time after an initial decline during the first two weeks.
Although not wanting to be limited to a particular theory, the results
indicate that the early stage diffusion mechanism may be the primary
mechanism contributing to the release of the beneficial agent, while at
later stages, polymer degradation might significantly contribute to the
release.

In Vivo Studies on Bupivacaine Depot Composition with Different PLGA
Molecular Weight Distributions

[0232] A representative number of implantable gels as tabulated in Table 2
were tested for in rats to determine vivo release rate profiles as
described in Example 15 above. In particular, depot gel bupivacaine
compositions were injected from customized 0.5 cc disposable syringes
having disposable 18 gauge needles, into rats and blood was drawn at
specified time intervals (1 hour, 4 hours and on days 1, 2, 5, 7, 9 and
14, 21 and 28) and analyzed for bupivacaine using LC/MS. FIG. 12
illustrates the representative in vivo release profiles of bupivacaine
obtained in rats from the formulations 11 and 12 (the bupivacaine depots
were formulated with the PLGAs with two different molecular weight
distributions in benzyl benzoate (single-modal containing MMW PLGA RG502,
and bi-modal mixture of HMW PLGA RG503 with LMW PLGA, Table 2
formulations 11 and 12).

[0233] A representative number of implantable gels as tabulated in Tables
7-9 were tested for in rats to determine vivo release rate profiles as
described in Example 15 above. In particular, release rate profile of
leuprolide was determined by measuring the blood serum or plasma
concentrations of leuprolide as a function of time, as illustrated in
FIGS. 13-16.

[0235] As illustrated in FIGS. 13-16, sustained release of leuprolide
acetate from the depot formulation of the invention can be achieved for a
duration of about 3 months to 6 months after administration. The release
profiles of the active agent from the depots can be varied by varying the
type of polymer and solvent, and by varying the polymer/solvent ratios.

[0236] A representative number of implantable gels as tabulated in Table
10 were tested for in rats to determine vivo release rate profiles as
described in Example 15 above. In particular, release rate profile of
leuprolide was determined by measuring the blood serum or plasma
concentrations of leuprolide as a function of time, as illustrated in
FIG. 17.

[0238] As illustrated in FIG. 17, sustained release of leuprolide acetate
from the depots formulation of the invention can be achieved for a
duration greater than or equal to 6 months by using the biodegradable
polymer with longer degradation duration. The release profiles of the
active agent from the depots can be varied by varying the type of polymer
and solvent, and by varying the polymer/solvent ratios.

EXAMPLE 22

In Vivo Release Rate Profiles of Various BuprEnorphine Depot Formulations

[0239] A representative number of implantable buprenorphine depot gel
formulations of the present invention are tested for in rats to determine
vivo release rate profiles as described in Example 15 above. In
particular, release rate profile of buprenorphine is determined by
measuring the blood serum or plasma concentrations of leuprolide as a
function of time. The release profiles of the active agent from the
depots can be varied by varying the type of polymer and solvent, and by
varying the polymer/solvent ratios.

EXAMPLE 23

In Vivo Testosterone Suppression by Depot Gel Leuprolide Formulations

[0240] In general, in vivo studies in rats were performed following an
open protocol to determine plasma levels of leuprolide upon systemic
administration of leuprolide via the implant systems of this invention.
Depot gel leuprolide formulations (prepared as described in Examples
above) were loaded into 0.25 cc Hamilton Gastight syringes. Disposable 18
gauge needles were attached to the syringes and were heated to 37.degree.
C. using a circulator bath. Depot gel leuprolide acetate formulations
were injected into rats and blood was drawn at specified time intervals.
All plasma samples were stored at 4.degree. C. prior to analysis. Samples
were analyzed for leuprolide as described in Example 15 above, and for
testosterone using a commercially available RIA kit (DSL-4000) (Ricerca,
LLC, Painesville, Ohio).

EXAMPLE 24

In Vivo Release Rate Profiles and Efficacy of Various Leuprolide Acetate
Depot Formulations

[0241] A representative number of implantable gels as tabulated in Table
11 were tested for in rats to determine vivo release rate profiles and
efficacy as measured by testosterone suppression as described in Example
23 above. In particular, release rate profile of leuprolide and efficacy,
i.e. testosterone suppression, were determined by measuring the blood
serum or plasma concentrations of leuprolide and testosterone as a
function of time, as illustrated in FIG. 18.

[0242] In particular, FIG. 18 illustrates representative in vivo sustained
release profiles of leuprolide acetate obtained in rats from depot
formulations according to the present invention containing PLGA (L/G:
75/25) in both benzyl benzoate (BB) and benzyl alcohol (BA) for 3 months
(formulations 54 and 55). FIG. 19 illustrates the testosterone profiles
of the leuprolide acetate depot formulations (formulations 54 and 55) as
compared to placebo depot formulation without leuprolide acetate
(formulations 56 and 57). The leuprolide acetate depot formulations
exhibited sustained release rate profiles for prolonged period of time, a
duration greater than or equal to 3 months, and were efficacious in
suppression of testosterone level in the rats to their castration level
(<0.5 ng/mL) after 10-14 days as compared to the placebo formulations
(4-5 ng/mL).

EXAMPLE 25

In Vivo Release Rate Profiles and Efficacy of Various Leuprolide Acetate
Depot Formulations

[0243] A representative number of implantable gels as tabulated in Table
12 were tested for in rats to determine vivo release rate profiles and
efficacy as measured by testosterone suppression as described in Example
23 above. In particular, release rate profile of leuprolide and efficacy,
i.e. testosterone suppression, were determined by measuring the blood
serum or plasma concentrations of leuprolide and testosterone as a
function of time, as illustrated in FIG. 20.

[0244] In particular, FIG. 20 illustrates representative in vivo sustained
release profiles of leuprolide acetate obtained in rats from depot
formulations according to the present invention containing P(DL)LA in
either benzyl benzoate (BB) or benzyl alcohol (BA) for 6 months
(formulations 58 and 59). FIG. 21 illustrates the testosterone profiles
of the leuprolide acetate depot formulations (formulations 58 and 59) as
compared to the placebos without leuprolide acetate (formulation 60 and
61). The leuprolide acetate depot formulations exhibited sustained
release rate profiles for prolonged period of time, a duration greater
than or equal to 6 months, and were efficacious in suppression of
testosterone level in the rats to their castration level (<0.5 ng/mL)
after 10-14 days as compared to the placebo formulations (4-5 ng/mL).

EXAMPLE 26

[0245] The above-described exemplary embodiments are intended to be
illustrative in all respects, rather than restrictive, of the present
invention. Thus the present invention is capable of many variations in
detailed implementation that can be derived from the description
contained herein by a person skilled in the art. All such variations and
modifications are considered to be within the scope and spirit of the
present invention.